1111possibly stroke and heart attack). These new blood vessels are highly damaging as they often fail to deliver a sufficient blood supply, leak fluid and can rupture causing tissue haemorrhage. As a consequence, dysfunctional vessels contribute towards the incidence of a disease (morbidity) and the death rate amongst patients (mortality) associated with many diseases.
Although considerable advances have been made in preventing abnormal vessel growth in the eye, it may be preferable to devise new therapies that prevent the early blood vessel changes that underpin abnormal vessel growth or, when they do occur, promote the growth of normal vessels. The Greenwood and Moss labs have discovered a molecule called LRG1 that is increased in many diseases and which disrupts normal existing vessels as well as promoting the growth of dysfunctional vessels. Following the development of a therapeutic agent (Magacizumab) that blocks the disrupting effect of LRG1, the Greenwood and Moss teams have found that they can improve vessel function and reduce abnormal vessel growth not only in the eye but also in solid cancers.
This finding that inhibition of LRG1 reduces early vascular dysfunction, that often precedes the onset of new vessel growth, raises the possibility that earlier intervention in diseases such as diabetic retinopathy may be possible. This new therapy will enter into clinical trials at Moorfields Eye Hospital in 2018 for the treatment of wet age-related macular degeneration with the aim of taking this forward for the treatment of diabetic retinopathy shortly afterwards.
In conclusion, despite the many years it takes (sometimes 15-20 years) from discovery to patient benefit, this work demonstrates the importance of discovery science as this allows for greater step changes in new treatments to be achieved. Taking what is known and tinkering with it only delivers small incremental improvements and the way medicine is going shows that single treatments are insufficient and providers of eyecare will need to use combination therapies to enhance efficacy.
2.3 The genetic revolution
Dr Denize Atan
SOCS Lead for Women in Science
Consultant Senior Lecturer in Ophthalmology
School of Clinical Sciences
F38, Biomedical Sciences Building
University of Bristol
We are in the midst of a genetic revolution. Advances such as the Human Genome Project, HapMap, 1000 genomes and innovations in sequencing technology mean that we now know much more about the human DNA sequence and the role of non-coding DNA in regulating which genes are switched on or off, in which cells and at what time during development. We can determine who has inherited certain genetic faults that will inevitably lead to disease but also who has inherited a high genetic risk of future disease.
Eye research has proceeded in these two directions:
a.) To identify genetic variants that increase risk of a disease.
For example, normal variants in the complement factor H gene determine whether an individual is at very high risk of developing age-related macular degeneration. Drs Denize Atan and Amanda Churchill have identified variants in the VEGF gene that are also associated with AMD. There are many variants in other genes that also modify the genetic risk of AMD. In other words, there are several genetic variants that combined together alter risk of AMD. An individual’s genetic risk of AMD is determined by the combination of all of these genetic variants.
Though an individual’s combined genetic risk might be high, there are also environmental risk factors that interact with our genes to actually cause disease. For AMD, these include smoking, high blood pressure, exposure to sunlight, poor diet. This means that if an individual finds they have a high genetic risk of developing AMD in future, they may prevent the onset of disease by making sure they do not smoke, eat a healthy diet, exercise, avoid sun exposure, control their blood pressure etc.
In addition, Dr Atan has identified variants in the TNF and IL10 genes that alter risk and severity of uveitis, an inflammatory disease of the eye that can impair the vision of young working age adults. The treatment of uveitis is with strong immunosuppressive drugs which frequently cause serious side-effects. If we know which individuals are genetically predisposed to severe disease, we can treat them more aggressively from the outset to preserve vision.
The general public are interested in determining their genetic risk and severity of disease as evidenced by the expansion of private companies that offer whole genome DNA sequencing as a commercial service and will report on an individual’s genetic risk for different types of disease. For example, 23andme offer this service for £129 (https://www.23andme.com/en-gb/).
b.) To identify causes of genetic disease.
This research is particularly pertinent in the age of gene therapy. It is not possible to treat a patient with gene therapy if the gene at fault has not been identified first. Combined with imaging technology to diagnose patients with a retinal disorder at an earlier age, early genetic diagnosis means the ability to deliver gene therapy at an earlier stage and while the retina is still developing postnatally so that the effects of the mutation are mitigated. Research by Dr Denize Atan has identified a gene called PRDM8 that is implicated in congenital stationary night blindness – an early onset blinding disorder that could be treated with gene therapy if identified sooner.
In the NHS, genetic screening for inherited retinal diseases is an iterative process (repetitive rounds of analysis). Individuals with a certain pattern of symptoms, signs or syndrome that is thought to be due to an inherited disease will be tested against a panel of the most common genetic mutations to cause that disease. If the first round of tests is negative, patient DNA might be tested against a second panel of less common variants. They might be tested for large DNA deletions or duplications. But if more detailed tests are not available on the NHS, they will be left in the dark about what has caused their disease. Sometimes, doctors send DNA samples to research labs with an interest in a particular disease to test patient DNA for less common mutations, on the presumption that the lab has the funding, interest and good will to do more detailed tests. There is also the 100,000 genomes project that offers DNA sequencing for individuals with rare undiagnosed syndromes and cancer.
As the cost of whole genome sequencing has dramatically reduced in recent years, it is likely to become more cost effective to sequence the whole genome of patients from the outset (e.g. 23and me) rather than the stepwise targeted approach described above. The challenge will be how we process and analyse this data from whole genome sequencing, which is computationally intensive.
2.4 From basic cell biology to ocular disease and new therapies
Professor Karl Matter
Professor of Cell Biology
UCL Institute of Ophthalmology, UCL, London
Tissues and organs in our bodies are formed by sheets of cells that interact with each other via molecular complexes that join the cells together and seal the gaps between neighbouring cells. These complexes do not just act as glue: they function as sensors that transmit information to the cell interior about the environment, such as the presence or absence of neighbouring cells or whether the neighbouring cells are in a normal or stressed state. This sensing mechanism guides tissue formation and maintenance, and how tissues respond to damage and different types of stress such as inflammation. In the eye, examples of such cell sheets include the corneal epithelium, a cell sheet that protects the surface of the eye, and the retinal pigment epithelium at the back of the eye, a cell layer that supports the survival and function of photoreceptors, the cells that harvest light and directly mediate vision. The photoreceptors themselves also form a layer of cells by interacting with each other. Defects in the mechanisms by which cells interact with each other cause serious diseases that lead to strongly reduced vision and blindness. Examples include retinitis pigmentosa, an inherited disease leading to blindness due to defects in photoreceptors and the retinal pigment epithelium, and acute and chronic inflammatory conditions affecting the ocular surface and the retinal pigment epithelium.
There is ongoing investigation into the molecular mechanisms by which cells interact with others and how they transmit information to cells and guide their behaviour. These mechanisms have been discovered by using cell biological approaches and by questioning if and how they play a role in human disease and understanding if it is possible to manipulate these mechanisms to treat such diseases.
Example 1 – 15 years ago, we discovered a new component of cell-cell interactions that we are targeting now to develop therapies for inflammatory diseases. Chronic inflammatory diseases of the ocular surface (e.g., conjunctivitis) and the retina (e.g., uveitis) are very common and difficult to treat effectively. Inflammation is also a major driver of age-related macula degeneration, a very common cause of reduced vision and blindness. Debilitating chronic, allergic and autoimmune inflammatory diseases affect other organs in our bodies such as the lungs (e.g., chronic obstructive pulmonary disease) and the nervous system (e.g., multiple sclerosis) and, as in the eye, are generally difficult to treat effectively.
Subsequent research demonstrated that this protein signals to cells and thereby controls cell behaviour and survival. Using samples from human eyes and tissues donated to research, we found that this protein is expressed at very low levels in healthy tissue but is unregulated in response to inflammation and other forms of tissue damage such as wounding. We therefore asked whether inhibition of this signaling protein can block inflammation and degenerative processes leading to blindness.
To do so, we have developed a group of molecules that can block the function of this signalling protein. We then demonstrated that these molecules indeed work in cultured cells of different types that play an important role in inflammatory eye diseases. We are now testing the more effective of these molecules in disease models with the aim to start clinical trials once these experiments are completed. The aim is the development of therapeutic drugs that are either applied locally (e.g., eye drops for ocular diseases) or to the entire body (e.g., pills/injections for internal organs).
Example 2 – We postulated that cells make molecules that help them form and stabilise cell-cell interactions. By looking at a distinct group of molecules encoded in our genes, we discovered such a molecule that is required for the formation of stable cell-cell interactions in many different tissues. Last year, we discovered that inherited defects in this molecule cause retinitis pigmentosa.
We now started to investigate how these defective molecules induce disease and to explore different strategies to correct malfunctioning of this molecule with the aim to develop an effective therapy. This research is at an early stage but we have already made significant progress as we can rely on tools that we have developed over the last years. The aim of this project is to develop a therapy based on replacing the defective gene (e.g., gene therapy). For this purpose, we are now generating disease models that we can study and manipulate in the laboratory that are based on cells obtained from patients and hence carry the defective gene.
Example 3 – Cells do not only interact with neighbouring cells within the same sheet but they also provide support for neighbouring cells. For example, the retinal pigment epithelium is important for vision because it supports the functions for photoreceptors that reside on top of the retinal pigment epithelium. Photoreceptors develop a specialized domain that senses light and they constantly renew this domain, which is important to maintain their function. This renewal process involves the shedding of old material, which needs to be removed to maintain functionality of the retina.
Removal of this old material is mediated by the retinal pigment epithelium, which internalizes this debris and breaks it down. This internalization process is called phagocytosis. If the retinal pigment epithelium is defective, phagocytosis does not occur, the shed photoreceptor debris accumulates, and the retina degenerates.
We discovered a new molecule responsible for activating phagocytosis. Phagocytosis requires a molecular motor; an engine that drives the internalization of debris: the molecule we discovered turns on this motor. In cells form patients that suffer of retinitis pigmentosa because of defects in phagocytosis, this molecule is not activated. Thus, we now investigate how we can activate this molecule and the motor to rescue phagocytosis with the aim to prevent the loss of vision in patients with defective phagocytosis due to retinitis pigmentosa or age-related disease. We aim to develop different approaches for drug-based therapies to determine the most effective and safest approaches to rescue phagocytosis in patients.
2.5 Studying gene-gene interaction and gene-environment interaction in support of preventative therapies
Professor Sobha Sivaprasad
University College London
Consultant, Moorfields Eye Hospital
There are no preventive measures for age related macular degeneration. One of the challenges in drug discovery in this area is the heterogeneous nature of AMD. Several genes and environmental risk factors also contribute to the disease. Therefore, in order to study preventive options, it is crucial to recruit a study cohort of people aged 65 years or above and to study the gene-gene interaction and gene-environment interactions and their influence on AMD development and progression over time. This will involve recruiting a large population of Caucasian people aged 65 years or above irrespective of the presence or absence of AMD and studying the above risk factors and correlating them to the macula features using multimodal imaging and visual function tests. They will then need to be followed up 3 years later to study rate of progression of AMD to identify patients that are best suited to study preventive options.
This study will provide the UK with firstly a well characterised cohort of older individuals to study, secondly provide novel information on gene-gene interaction and gene-environment interaction to understand disease mechanisms and thirdly an enriched cohort of patients that can contribute to clinical trials on prevention of AMD.
2.6 Understanding disease mechanisms with post mortem eye disease models
Dr Marcus Fruttiger
Reader – UCL Institute of Ophthalmology, London
The human eye is one of the few organs where it is virtually impossible to take biopsies, and consequently it is difficult to investigate mechanisms of eye diseases directly. To get around this problem, scientists often use model systems, such as mice and rats. This approach offers very valuable insights into the basic biological processes that can occur, but has the disadvantage that it does not inform us directly about what processes actually do occur in human patients. Consequently, promising looking trials in preclinical models often fail in human patients. Therefore, a more detailed understanding of human disease mechanisms is a key prerequisite to improve current translational approaches. To address this knowledge gap we are using human postmortem tissue from eye donors with specific eye diseases and investigate whether current ideas about retinal disease processes can be confirmed. This can provide important guidance for the development of the next generation of therapies that are aimed at curing eye diseases.
2.7 Alternative models for studying complex diseases
Professor Majlinda Lako, PhD
Professor of Stem Cell Sciences
Institute of Genetic Medicine and Institute for Ageing
International Centre for Life
Newcastle upon Tyne
One of the problems with studying Age related macular degeneration (AMD) is that the affected retinal tissue is difficult to obtain, there are no animal models that faithfully mimic the disease and human trials are long and costly. So, Professor Majlinda Lako’s team at Newcastle University has created two (stem cell) disease models focusing on age-related macular degeneration (AMD) and Retinitis Pigmentosa (RP).
In relation to AMD, the disease model for patients is designed with the most common genetic risk factors for the disease. Data shows that this model mimics the key features of AMD and can be used to test new therapies and to better understand the pathology of disease and the role of environmental, dietary and lifestyle factors.
Also, new retinitis pigmentosa (RP) models have been created, allowing researchers to design therapeutic interventions (for example gene editing/gene therapy in RP) and test its feasibility/success in a lab model before moving it to the clinic as well as to test new drugs and repurpose current drugs
The retina is a highly metabolic organ whose function depends on the proper function of a large number of genes assembled together in various combinations through a process called splicing. One of the most common causes of RP is a fault in a group of genes that regulate this process. Despite this defect residing in all cells of the body, the retina is mysteriously the only tissue affected which makes deriving new treatments difficult and so these disease models can unlock some of these mysteries. Other benefits of using such disease models include applying this knowledge to other organ systems e.g kidney disease, Providing a platform to validate clinical trial strategies and to study complex diseases (such as AMD) and to fully validate the role of other factors (dietary, lifestyle etc) in addition to genetic susceptibility
Also, these disease platforms are relatively inexpensive compared to clinical trials and current drug screening pipelines.
2.8 Understanding the role of the immune system in eye disease
Dr Colin Chu
NIHR clinical lecturer, Bristol Eye Hospital and University of Bristol
In early laboratory work, Dr Colin Chu and collaborators at UCL Institute of Ophthalmology discovered that an angiogram dye that has been widely used in hospitals for decades can actually bind to immune cells. This results in them fluorescing so they can then be seen in both the blood and the eye. This is an exciting finding and could increase our understanding of the immune system contribution to many eye diseases by permitting these otherwise invisible cells to be seen in the eyes of living patients. This technique could also possibly identify early relapse of disease and allow for the precise adjustment of the doses of medications until a cell response is seen.
Dr Colin Chu is starting a systematic clinical study of the dye in humans, which has not been performed before. It will identify the correct timings and circumstances in which cells can be seen in a selected range of eye diseases. Blood will also be taken and examined in the laboratory to check if the dye-labelled cells can be seen and check that there is no toxic effects upon them. If these studies are successful they will lay the foundation for a larger grant which could optimise the dye delivery and analysis methods to bring the technique to international availability.
2.9 Understanding Biology to Develop Novel Therapies or Molecular Therapies for Ocular Scarring
Professor Colin Willoughby
Professor of Molecular Ophthalmology
Institute of Ageing and Chronic Disease
University of Liverpool
In a healthy eye, a constant pressure is maintained by continuously producing fluid (called aqueous humour) while an equal amount of the fluid drains out of the eye through what’s known as the trabecular meshwork. However, in glaucoma patients (of whom there are approx. 12.5m worldwide and accounting for 1 in 10 blind registrations in the UK), the trabecular meshwork becomes blocked over time thus increasing pressure in the eye (so called Intraocular Pressure or IOP), resulting in damage to the optic nerve and serious, irreversible sight loss if left untreated.
It has been observed that a protein called TGFβ is increased in the aqueous humour of glaucoma patients and in the most common type of glaucoma, known as ‘primary open-angle glaucoma’(POAG), but unfortunately the current pharmacological agents do not target the effects of TGFβ which damages the trabecular meshwork producing raised IOP, therefore leaving the disease in the trabecular meshwork entirely unchecked and the resulting higher IOP may then require further medical or surgical interventions.
There is even worse news – with surgery, the aqueous humour is directed under the lining of the eye (conjunctiva) but as it still contains TGFβ there is a scarring response which can result in failure of the operation to control IOP and stabilise the disease. This scarring response under the conjunctival involves cells called Tenon fibroblasts and surgeons use potent and toxic anti-cancer drugs to prevent scarring and surgical failure which have significant sight-threatening side effects.
In light of this, Professor Colin Willoughby and his team at Liverpool University have identified small, naturally occurring regulatory genes called microRNAs which target TGFβ and that can be manipulated therapeutically: ‘GlaucoMirs’. Therefore he aims to develop miRNA-based therapeutics (GlaucoMirs) to treat TGFβ induced fibrosis in the trabecular meshwork and in Tenon fibroblasts to improve the treatment of glaucoma medically and surgically. He aims to provide significant insights into the molecular changes that cause glaucoma in the trabecular meshwork and data drawn from computer analysis and genetic sequencing of cells drawn from his cell bank will allow them to develop a new class of disease-modifying therapeutics targeting TGFβ in glaucoma based on miRNA biology.
Excitingly, the implications of this work can transcend glaucoma and miRNA-based therapeutic approaches could be directed to other TGFβ driven ocular scarring: corneal disease and retinal scarring in diabetic eye disease, AMD and following retinal detachment surgery.
2.10 The need to move from rehabilitation to effective treatment strategies for rare eye diseases
Professor Marcela Votruba
Head of School
School of Optometry & Vision Sciences
Inherited mitochondrial eye diseases are rare diseases. Some startling facts:
- 1 in 17 people, or 7% of the population, will be affected by a rare disease at some point in their lives.
- This equates to approximately 3.5 million people in the UK. 80% of rare diseases have a genetic component.
- There are over 6000 rare diseases but only 126 rare disease medicines in Europe.
The UK Government and Devolved Nations have all signed up to the rare Disease Plan and slowly there are growing signs of implementation strategies. However, progress for patients with rare diseases is slow.
One group of rare diseases that affect the eye are mitochondrial diseases, including those affecting the eye primarily, and they are an important cause of vision loss. The chief reason for vision loss is optic atrophy or neuropathy. Recently, this group of inherited conditions have become better understood as mitochondrial optic neuropathies and the two commonest conditions are Leber’s hereditary optic neuropathy and dominant optic atrophy.
Mitochondrial optic neuropathies affect an estimated 1 in 10,000 individuals, especially among children and young adults. The pathological hallmark is the preferential loss of retinal ganglion cells (RGCs) within the inner retina, which results in progressive optic nerve dysfunction and the onset of visual symptoms. The past 25 years has seen tremendous progress in our understanding of the molecular genetic basis of this group of disorders, providing at the same time invaluable insight into the shared disease pathways that precipitate retinal ganglian cell (RGC) loss. The devastating visual loss, which is almost always irreversible, lacks effective treatments and management is currently largely supportive aimed at visual and occupational rehabilitation.
So, significant resources will need to be invested in an effort to develop effective treatment strategies aimed at rescuing RGCs . There are promising avenues of research. However, the fast tracking of translational breakthroughs for inherited optic neuropathies will not be possible without funding and collaboration across academic, clinical translational and commercial sectors.
2.11 Understanding disease mechanisms to improve selection of treatments, identify targets for therapy and increase personalisation of therapies with reference to Uveitis
Professor Sue Lightman
Professor of Clinical Ophthalmology at University College London (UCL) and
Institute of Ophthalmology (IOO)
Consultant Ophthalmologist, Moorfields Eye Hospital, Hammersmith Hospital
and Royal Surrey County Hospital.
- Understanding disease mechanisms in Uveitis and using different drugs such as those applied to arthritic patients
- Understanding disease mechanisms in uveitis by using Animal models of disease, particularly rodent models. Use of different drugs targeting key cells led to introduction of new and more successful drug treatments
- Understanding mechanisms of disease in different types of uveitis led to identifying various Cell lines derived from ocular fluids from patients with different types of uveitis. Their modulation by different drugs led to the introduction of new therapies for patients based on this understanding
- Understanding how fluid gets into the retina and causes visual loss in patients with uveitis, followed by measuring the permeability of the normal blood retinal barrier and then looked at what inflammatory cytokines disrupt it (using rodents) and looked at effect of cytokines injected into the eye. This has led to knowledge of which were the important cytokines in causing the fluid and visual loss and introduction of novel therapeutic options
- Understanding how to personalise treatment for patients with uveitis by understanding which drugs can modulate their immune system to allow the patient to control the inflammation. This is very new research and will lead to patients receiving personalised immune testing against different drugs
- Understanding pathogenesis of scleritis which was originally thought to be due to innuendo complex disease. Biopsies of lesions in patients with scleritis have led to knowledge of T cell involvement and changed management of this disorder
- Looking at factors that predict disease outcome in patients with uveitis, such as genetic factors and ocular risk factors which have led to more aggressive disease management
- Biopsies of the conjuctiva in different types of severe allergic conjunctivitis have led to a better understanding of the 2 major types which have different disease mechanisms. More successful treatment regimes targeted the key cells in each disorder reducing the incidence of blindness
- In patients undergoing organ transplantation or those with other severe immune mediated diseases, mycophenolate was found to be a very successful drug. As a result, this drug was introduced in pilot studies into patients with immune mediated eye disease where it has been very effective. Similarly the use of biological in patients with arthritic disorders led to successful pilot studies in patients with eye disease and then their wider instructions to the benefit of many patients
2.12 Understanding response, repair and regeneration mechanisms in ocular tissue to improve treatments and patient care
Professor Baljean Dhillon
Professor of Clinical Ophthalmology, University of Edinburgh
Hon. Consultant Ophthalmology
Princess Alexandra Eye Pavilion
The eye offers a unique window on tissue repair and regeneration. Current work includes molecular diagnostics of the aging lens, limbal stem cell disease and replacement and mechanisms/modelling of inherited and age-related retinal disease. Professor Dhillon and his team have identified potential methods to ameliorate and reverse protein unfolding in the crystalline lens, restore limbal stem cell function and deliver in vitro readouts in retinal disease for mass drug screening for the prevention and progression of disease.
Their collaborations between chemistry, engineering and physics to image and investigate light-tissue interactions specifically UV-induced damage and oxidative stress will underpin a deeper understanding of how best to detect lens, limbal and retinal tissue response and repair in health and disease. Novel imaging tools based on SPAD sensors, Raman and OCT in development, share synergies with optical imaging research. The capability to directly observe ocular tissues enables Professor Dhillon and his team to usefully apply and interrogate sensor capability in the eye allowing cross-fertilisation between research groups.
The relevance to neurodegenerative diseases is based on the shared origins and parallel pathways between eye and brain, for example MS-related optic nerve inflammation and subsequent atrophy. Optic nerve regeneration requires close integration across different disciplines and research groups in assessing efficacy of regenerative strategies. Cross-disciplinary collaboration is the key to linking and maximising the potential of inflammation and tissue repair research relevant to restoring sight and enhancing patient care.
In summary, Professor Dhillon’s intention is to identify more effective and less invasive approaches which might usefully be applied earlier in the disease process. As a result, they will be safer and achieve a better tissue response ,improving the likelihood of visual restoration and producing better outcomes for patients.
2.13 Progress in Molecular Diagnostics and Therapeutics for corneal eye disease
Moore Research Group, Ulster University, Northern Ireland.
The research team lead by Professor Tara Moore at Ulster University is conducting world-leading ophthalmology research which directly impacts upon clinical outcomes for both diagnostics and therapeutics of eye disease. The team specialises in discovery of specific genes linked to inherited eye disease. Likewise, their ability to modify the genome has emerged as a promising therapy for inherited diseases that otherwise have no effective treatment. Recent advances in the field of genome engineering have provided tools to more easily manipulate genomic DNA sequence. CRISPR/Cas9 gene editing, when programmed by the Moore research team, can find amongst the billions of DNA bases of the genome the one mistake which causes disease. This results in gene knockout or correction of the causative defect. In the era of personalised medicine, by knowing the DNA sequence of an individual and detecting the mistakes which relate to disease, pre-screening of all family members allows a bespoke gene therapy to be designed and administered prior to disease symptoms developing.
Ocular genetic disease offers distinct benefits in the field of genome engineering. A high proportion of ocular diseases are monogenic and the causative gene has been elucidated in many cases. In addition, the eye offers unique anatomical and physiological qualities that make it amenable to treatment; it is easily accessible, has a small surface area and holds an immune-privileged status making ocular diseases an ideal system in which to develop for CRISPR/Cas9 gene therapy.
The advancements in genome engineering have accelerated the prospect of personalised medicine as a therapeutic option. Currently Editas Medicine have a clinical trial planned for Leber congenital amaurosis (LCA) where CRISPR will be targeted to remove the mutation in CEP290 which otherwise causes mis-splicing of the mRNA. They recently announced future plans for a similar trial targeted to Usher syndrome. It is likely these initial clinical trials will pave the way for treatment of a number of similar ocular disorders. Indeed, using ocular diseases as a model it is conceivable that soon an array of therapeutics will materialise that will allow safe and efficient correction of a range of genetic defects beyond ocular diseases.
The idea of personalised medicine can extend beyond the gene therapy paradigm. If an individual harbours certain mutations this can act to influence their response to certain environmental stimuli. For instance, we have shown patients receiving laser eye surgery, who carry a mutation in TGFBI associated with corneal dystrophy, present with an accelerated deposition of mutant protein occurs, which otherwise would not be produced. Professor Moore concurrently holds a position as Director of Research and Development at Avellino Labs USA which provide a genetic screen for TGFBI mutations. This allows candidates for refractive surgery to be advised on the risk of adverse pathology post corrective laser eye surgery and to date they have tested over 700,000 individuals and prevented over 600 people from having a potentially blinding reaction post laser eye surgery. Another example includes the link between ultraviolet (UV) light in the development of pterygium, a disease that presents at the front of the eye as a growth of cells which blocks vision. The Moore research team at Ulster have discovered the existence of a feedback loop, protecting against UV exposure and has identified novel mutations in these patients that hinder this protective capacity.
The team’s continual drive and passion to understand genetic variants associated with monogenic disease, for which a single gene is accountable, has demonstrated new and novel treatment options. Efforts must now extend to complex diseases that require a greater appreciation of not only genetic variants, but the regulatory influences that contribute to disease.
2.14 Complement as a driver of age-related macular degeneration
Claire L Harris
Professor of Immunology
Complement Therapeutics Research Group/National Renal Complement Therapeutics Centre
Institute of Cellular Medicine
Faculty of Medical Sciences
Complement is a component of the immune system best known for its ability to attack foreign cells and ‘punch holes’ in their membrane causing an explosion of cell contents and consequently, cell death. It does this by forming a transmembrane lytic pore called the membrane attack complex, or MAC. The process of complement activation also results in deposition of the activated central complement protein, C3b, on to particulate surfaces such as infectious agents, dead cells and debris. These deposited fragments help to ‘flag’ the particles for removal by cells of the immune system, this process keeps tissues healthy.
However, a dysregulated complement system can cause a lot of harm, and all the signs point to this in age-related macular degeneration (AMD). In 2005, the complement field was energised by the publication of several genome-wide association studies (GWAS) and candidate gene studies evidencing strong genetic association between a chromosome 1 gene encoding a key complement control protein, factor H (CFH), and risk for AMD. In the following few years, further studies illustrated disease risk associated with other complement genes. These genetic variations, although relatively common in the normal population, were particularly high in the AMD population. Additional data showed that the fatty, retinal deposits, ‘drusen’, the hallmarks of early AMD, were coated in high levels of C3 fragments and MAC, confirming that complement was active in the retina. Together, thesedata provided compelling evidence for a role of complement in AMD and suggested that the complement system might actually be doing more harm than good (Anderson et al. The pivotal role of the complement system in aging and age-related macular degeneration: hypothesis re-visited. Prog Retin Eye Res. (2010) 29:95).
Despite the association of gene variants with disease, it was still unclear how complement contributed to development of AMD. Prof Harris and colleagues set out to explore whether the variant proteins arising from these disease-associated genes, changed the way in which the complement system worked. They purified the variant proteins from the plasma of healthy people and teased out the functional differences using highly sensitive laboratory analytical processes. In all cases, the AMD-risk variants of these proteins made the complement system more active, whereas those which lowered risk of AMD generated a less ‘vigorous’ complement system (Harris et al. The complotype: dictating risk for inflammation and infection. Trends Immunol. (2012) 33:513). In parallel work, others showed that people with the risk variants of these proteins also carried higher levels of activated complement products in their blood (‘biomarkers’), strengthening the concept that a highly active complement system was somehow driving the development of AMD.
These data have fed the appetite of academics, small companies and big Pharma alike to develop drugs targeting complement (Morgan & Harris. Complement, a target for therapy in inflammatory and degenerative diseases. Nat Rev Drug Discov. (2015) 14:857). The drug development landscape is bursting with agents progressing through clinical phases and destined for therapy in AMD. Most assets target C3 activation, although some target downstream and prevent MAC formation. The most advanced, lampalizumab, has shown promise in phase 2 by slowing progression of retinal atrophy and is now in phase 3 for geographic atrophy (GA). Interestingly, outcome analysis of patients in the trial indicated that the ‘genetic make up’ of their complement system might impact therapeutic success; we eagerly anticipate data from the larger phase 3 trials (CHROMA & SPECTRI) which may provide invaluable insight into disease pathogenesis and treatment outcome.
It seems as though the role of complement in AMD is all ‘wrapped up’, but in reality there is a long way to go before we truly understand the complex aetiology of this disease. Questions remain, such as:
- The role of the seminal CFH variant found in both CFH and a gene splice product FHL1; it seems to have little impact on activity of the system, we and others speculate that it may play a role in surface localisation and subsequent control.
- The major contribution to disease risk from the non-complement genes, ARMS2/HTRA1 locus (chromosome 10). Are the chromosome 1- and chromosome 10-driven forms of disease distinct? Do these genes dictate the kind of therapy that might be of benefit?
- The systemic or local nature of the disease; controversy remains as to whether therapy should be provided locally in the eye, or systemically. Clearly systemic therapy (particularly oral) would suit a large patient population, particularly if consideration can be given to stopping progression of early disease.
- Our ability to ‘drug’ the complement system; complement is churned out at an enormous level by the liver and other tissues. Developing drugs that can dosed sub-cut or orally at practical levels is a challenge. Is intravitreal therapy the only option?
These questions, and others, are the subject of intense research by academia and drug companies alike. Research is progressing at a fast pace and we anticipate that the pieces of this confounding puzzle will soon come together to give us a clear picture of the pathogenesis of this complex disease.
2.15 Proteostasis mechanisms in healthy, ageing and diseased Retinal Pigment Epithelium: challenges and therapeutic opportunities for Age-related Macular Degeneration
Professor Luminita Paraoan
Professor of Molecular Cell Biology
Ocular Molecular Biology and Mechanisms of Disease Group Leader
Eye and Vision Science, Institute of Ageing and Chronic Disease
University of Liverpool
Age-related macular degeneration (AMD) is a complex disease characterised by a progressive degeneration of the central part of the retina (macula) directly linked to the dysfunction of the essential, supporting monolayer of cells – retinal pigment epithelium, RPE. The resulting serious visual impairment and blindness have been associated with a broad range of causative factors, both genetic and environmental, and ageing. Despite the multitude of these factors, multifaceted functional interactions between these highlighted a relatively small number of common fundamental cellular processes that are affected. In addition, increasing evidence from other age-related diseases that affect different parts of the central nervous system supports the notion that the impaired cellular processes are substantially similar especially in terms of abnormal extracellular deposits, metabolic and oxidative stress, inflammation and microvascular abnormalities, thus pointing to similar pathogenic cellular mechanisms.
While vision loss and blindness are not a normal part of ageing, age is one of the strongest risk factors for developing AMD/age-related degenerative diseases. All structures of the eye undergo ageing changes leading to varied effects. However, cells that maintain a non-proliferative state and a long lifespan, as well as their support structures – such as the retinal pigment epithelium and Bruch’s membrane, RPE/BrM, which are key sites for AMD pathogenesis – are particularly susceptible to age-related changes affecting essential cellular processes in the retina.
Proteostasis, or protein homeostasis, is a key achievement of cells that impacts critically on virtually every aspect of cell physiology, functions and lifespan. The cellular machinery that underpins proteostasis integrates complex, multi-layered regulatory networks that control the biogenesis, folding, trafficking and degradation of proteins present within and outside the cell. Loss of proteostasis, or failure of mechanisms responsible for maintenance of protein homeostasis, both intra- and extracellularly, is central to understanding the cause of AMD associated with different levels/forms of proteins, excessive protein misfolding, aggregation and degradation leading to loss-/gain-of-function phenotypes.
In this respect, the Ocular Molecular Biology and Mechanisms of Disease Group in the Department of Eye and Vision Science, University of Liverpool is studying various aspects of proteostasis that are essential for the normal functions of the RPE that become impaired in (neuro)degenerative processes. One area that the group has been focusing on is the identification and characterisation of the key effectors of proteolysis (protein degradation) and its regulation in healthy, ageing and diseased RPE cells. Specific proteolytic events, both intra- and extracellularly underpin major functions of the RPE – phagocytosis of spent photoreceptor outer segments, response to oxidative stress, authophagy, modulation of extracellular matrix, etc. The regulation of proteolysis therefore defines to a great extent RPE physiology and is implicated widely in pathophysiological processes associated with its ageing and disease. Not surprisingly from this point of view, the RPE invests a remarkable metabolic effort in synthesising and maintaining appropriate levels of a broad range of proteolytic enzymes and their inhibitors; these are some of the most abundantly expressed proteins by RPE; and one of the most potent regulators of proteolysis, the cysteine proteinase inhibitor cystatin C, is among the top 2% abundantly expressed genes by RPE. This inhibitor proved to be one of the models for studying mechanisms of impaired intracellular trafficking, organelles interactions, protein mis-processing and aggregation, imbalance of proteolytic activities. The basolateral secretion profile of cystatin C in RPE cells suggests a role in relation to maintaining the structure and function of Bruch’s membrane/choroid. A variant of cystatin C has been associated with increased risk of developing exudative age-related macular degeneration (AMD) and presents leader sequence-related dysfunctional intracellular trafficking, leading to reduced efficiency of processing through the secretory pathway, altered folding and increased aggregation. Remarkably, the same variant was the first one for which a genetic association for increased risk of both Alzheimer’s Diseases and AMD was described in different studies.
Overall the findings suggest that the RPE has a significant control over extracellular proteolytic events, via the secretion of highly active proteases, and their inhibitors. Molecular stress associated with natural ageing can alter the protease/inhibitor balance in/around RPE, which alongside misfolding of soluble proteins have the potential to contribute to pathological features of AMD, such as breakage of blood-retina barrier, formation of toxic aggregates, and structural abnormalities.
Evidence emerging from ours and other groups indicates that understanding of proteostasis as a salient feature shared by age-related and neurodegenerative processes is of outstanding importance for targeting early disease, for identifying interventions amenable to possible prevention or slow down of disease, and for rationale identification and design of more precise AMD therapies, efficiently targeting impaired intracellular trafficking, protein misfolding, aggregation and proteolytic imbalances.
3.0 Detection, diagnosis, measuring and monitoring
The ongoing developments of detection, diagnosis and monitoring of eye disease delivered bye the research community continue to highlight the critical role that new technologies, techniques and approaches play in disrupting conventional practice. They not only support improved prognosis, evidence based management of patients and the development of biomarkers but also help to validate and refine earlier, targeted therapeutic interventions alongside a (soon to be) cheaper and swifter diagnostic regime. The growth of clinicians’ knowledge about the impact of eye disease and the safety and actual effectiveness of treatments is also underpinned by a robust testing, measuring and monitoring regime. Such developments ensure that the momentum is maintained behind creating a more accessible, flexible, responsive eyehealth and eyecare service that emphasizes the need for greater patient self-care and individual responsibility and which can also impact on other areas of health.
3.1 The importance of accurate measurements to improve personalisation of treatments and management regimes for galucoma
Prof Ahmed Elsheikh PhD, CEng, MICE
Professor of Biomaterial Mechanics
Centre for Materials and Structures
Accurate measurements of internal eye pressure
Internal eye pressure (intraocular pressure, or IOP) is the only modifiable risk factor for glaucoma, the second most common cause of irreversible blindness, which affects approx. 500,000 people in the UK and 66 million people worldwide. The measurement of IOP is essential for the effective management of glaucoma, determining the amount of IOP-lowering medication and when to intervene surgically to enable a release of internal eye fluid.
Several techniques exist for the measurement of IOP, all of which rely on a simple concept. If a force is applied on the ocular surface (usually the cornea), the resistance of the eye to deformation is dependent on the IOP. While this concept is simple and easy to implement, it ignores the fact that the mechanical resistance of the eye plays an important role with, for example, thicker corneas offering more resistance than thinner corneas, and hence leading to an IOP overestimation.
Considering that the normal IOP range is small (10-21 mmHg), changes in corneal mechanical resistance (due to thickness or stiffness values that are different from average) may lead to either false negatives or false positives in glaucoma risk profiling, or lead to ineffective glaucoma management.
Our new method traces the corneal deformation under the force created by the measurement method, and uses the deformation magnitude and profile to estimate the effect of corneal mechanical resistance on the IOP measurement. Using this method, we have been able to produce IOP measurements that are independent of variations in corneal properties and hence more suitable for effective glaucoma management.
The new measurements have been assessed experimentally (on human donor eyes) and clinically, and the results have confirmed the accuracy of the IOP measurements. The method is now being extended to produce accurate estimations of the material behaviour of corneal tissue. If successful, the behaviour estimations have the potential to enable customisation of refractive surgeries, corneal implants, contact lenses and other treatment modalities to individual patient’s needs.
Continuous monitoring of internal eye pressure
Glaucoma is a progressive disease that leads, if badly managed, to irreversible blindness. The disease, which affects 66m people worldwide, is managed by reducing the eye’s internal pressure (intraocular pressure, or IOP) down to the normal levels of 10-21 mmHg.
Current practice relies on measuring IOP over a few minutes every 6 months and using the measurement to develop a management regime that relies either on IOP-lowering medication or surgery to halt glaucoma progression. However, it is known that IOP is dynamic, and changes continuously with sleeping and awakening, physical efforts, drinking, etc, and hence a snap-short measurement over a few minutes may not capture the true IOP effects. For this reason, efforts have been made for many years (>40 years) to continuously measure IOP.
Our new technology has been in development for 8 years and we now have an IOP sensor mounted on a soft contact lens and connected wirelessly to an external device that stores the IOP measurements for later analysis. The technology has been experimentally validated on both animal (porcine) and human donor eyes, and shown to provide accurate measurements of IOP.
We have just got MHRA and ethics approvals to test the technology clinically. Two studies will be conducted; a comfort test and a reliability test. The studies, which will involve 52 patients, are intended to produce initial results on the effectiveness of the device in the long-term IOP measurement. Further work will be needed to develop the technology into a market product and conduct a much wider clinical validation study.
If successful, the device could have a significant positive effect in the management of glaucoma patients and prevent their progression. Currently, about 15% of glaucoma patients lose their eye sight within 15 years of diagnosis, even whilst under treatment. This inadequate management outcome is thought to be caused by the inaccuracies caused by current IOP measurement techniques, and that a continuous measurement method would contribute to improved outcomes.
3.2 Peek innovation brings hope for society’s hardest to reach
Dr Andrew Bastawrous
Co-founder of Peek Vision, TED Fellow, Ophthalmologist, Clinical Lecturer
A clip-on camera adapter called “Peek Retina” that gives high quality images of the back of the eye and the retina has been launched from the UK, supported by a group of experts in technology, eyecare, business and engineering and inspired by ophthalmologist Dr Andrew Bastawrous’ experiences in providing eye care in Kenya.
Andrew and the team had been faced with using existing eye exam equipment which is heavy, expensive, fragile and difficult to use. It is not built to travel, it can feel intrusive and it needs a reliable supply of electricity to work. So his solution was to launch Peek which provides all the tools for professional eye exams from a smartphone with a clip on camera, combining both a traditional ophthalmoscope and a retinal camera in a mobile phone, providing a portable, less intrusive, more affordable and easier way to carry out comprehensive examinations. It sits neatly over the top of the device allowing a healthcare worker to easily take high-quality images of the back of the eye allowing them to diagnose cataracts, glaucoma and a range of eye diseases.
Peek Retina is one of a number of tools and programmes created by Peek to increase access to eye care.
The Peek team’s ethos can be outlined in Andrew’s comment below:
“What we are doing is not new, we just live in an era where we have new means to do it. Central to our work is our values: being quality driven, people-focused and acting with integrity. We are a family and we work together, as all families, with our imperfections. However, at our core is our shared vision and mission and we recognise that we can only realise our vision by working with others and for others. So many people have contributed to bring us to where we are now, and now more than ever we have a responsibility to reach those who are silently waiting”.
This stated ambition, passion and commitment shown by the Peek team has the potential to be applied to rolling out Peek across the UK to ensure that the so called “hard to reach” groups can benefit from the flexibility and diagnostic quality of Peek and many organisations have been in contact with Peek, reflecting a growing need for this technology. Such groups include the poorer socio-economic communities, prisoners, homeless, housebound and those in wheelchairs, residents in nursing homes and indeed those people who are unable to use standard desk-mounted equipment such as the obese and those with learning difficulties and dementia or who are unable to sit up straight or sit still.
This chimes with many initiatives supported by the voluntary sector, NHS England and stakeholders in eye care to encourage more preventative strategies and to support more community based eye care that is accessible, convenient, proactive and understandable to patients and which can ultimately ensure that pressure in secondary care is reduced while improving capacity and the ability to respond in the primary care sector.
So, Peek is poised to contribute to better eye health and primary eye care in the UK based on what it can contribute in a high income, strong health system setting (point solutions and systems) via the Peek Retina camera, Peek Acuity and additional smartphone based tests as they come online such as colour vision, contrast sensitivity and near vision. Indeed, Peek believes in strengthening health systems and empowering individuals and the potentially widespread availability of the Peek Acuity tests for school screening and Peek Retina for diabetic retinopathy screening programmes is testament to this laudable mission.
3.3 Better understanding technological performance in detection and treatment
Professor Augusto Azuara-Blanco
School of Medicine, Dentistry and Biomedical Sciences – Clinical Professor
Institute for Health Sciences
Centre for Public Health
Queen’s University, Belfast
All those active in eye research share a common goal of improving the quality of life and vision of people with eye diseases. Indeed, some researchers are focused on trying to better understand the mechanisms of eye diseases, which will bring forward the possibility of new treatments.
However, although these developments offer exciting possibilities, there is still a long process ahead before new treatments are confirmed as truly effective and safe. With this in mind, Professor Augusto Blanco and his team at Queen’s University Belfast are designing and conducting clinical trials of new technologies to determine if such developments are safe and can improve visual outcomes and indeed how they can best be adopted by the health services. For example, they are leading an EU-funded clinical trial that will test a laser prototype for open-angle glaucoma (OAG – the most common type) that is fully automated where the clinician simply presses a button and the equipment will recognise the location and deliver the laser treatment within 1 second. Another example is the large international EAGLE trial in 2016 which reported that clear-lens extraction surgery, similar to cataract surgery in treating Primary Open Angle Glaucoma (POAG which is more severe than OAG and is responsible for 2 out of 10 glaucomas in the UK) is superior to current treatment (with laser iridotomy to open the drainage pathways of the eyes) in terms of clinical outcomes, quality of life and value for money. Augusto Blanco and his team believe that the change in clinical practice will result in reduction of glaucoma blindness worldwide particularly in developing countries.
Professor Augusto Blanco is also interested in evaluating new diagnostic technologies. Accurate diagnostic tests can greatly help clinicians to timely detect eye diseases and start treatment early, and confirm that those without the disease do not need treatment. The rapid technological progress and the complexities involved in evaluating diagnostic tests were effectively outlined in a 2016 UK based diagnostic study (GATE – funded by NIHR) evaluating the imaging technology in the diagnosis of glaucoma and the ability to reduce the workload of ophthalmologists and improve accuracy.
3.4 How the application of machine learning and artificial intelligence (AI) can assist in the speed and quality of diagnosis
Dr Pearse A Keane
NIHR Clinician Scientist and Honorary Consultant Ophthalmologist
NIHR Biomedical Research Centre
Moorfields Eye Hospital NHS Foundation Trust and
UCL Institute of Ophthalmology
A collaborative Research venture is now progressing between Moorfield Hospital’s Dr Pearse Keane and Google’s DeepMind team led by the co-founder Mustafa Suleyman, aimed at developing ways in which Artificial Intelligence (AI) can be applied to ophthalmology and in particular to the type of imaging of the eye called Optical Coherence Tomography (OCT – an established medical imaging technique that uses light to capture 3-dimensional images).
Undoubtedly, the scanning of patients’ eyes using OCT (three-dimensional scans of the retina which is much better at revealing eye disease than traditional retina photography) heralded one of the biggest developments in modern ophthalmology – but unfortunately, the increasing number of false positive referrals received by hospitals like moorfields will soon be exacerbated by the imminent roll out of OCT devices amongst opticians who may not have the sufficient training to interpret the scans. These scans are quick, easy and safe to acquire, but too many patients are being referred for the wrong reasons, leading to a clogging up of the clinics and the resulting inability of clinicians to treat genuine cases of sight loss (e.g diabetic retinopathy or wet amd) within an appropriate time scale. This swamping of services could not be happening at a worse time. Ophthalmology is already the second-busiest speciality in the NHS, with more than 9 million outpatient appointments per year.
Therefore, how can the application of machine learning and AI assist in improving the quality and speed of diagnosis thus allowing for earlier and more effective treatment whilst reducing patient numbers and prioritizing those that require urgent treatment first? The answer is that generally, AI is delivering huge improvements on e.g speech recognition, very good translation, very good image labelling and image recognition. There are much improved machine learning models, access to very large-scale computers and there is increasingly enough training data to help build effective models.
So with that developmental momentum, the millions of OCT scans held by Moorfields has presented DeepMind with the ideal dataset for DeepMind to apply its research. In a way, DeepMind is replaying all of the scans to the machine learning system in the same way that an expert consultant ophthalmologist might sit in front of their computer and watch scans and case studies over and over again – this is what the DeepMind calls “experience replay”. The system being applied to the Moorfields data is “imagining” an abstract form of the disease it looks for such as Diabetic Retinopathy (DR) , seeing it in its “mind’s eye”. This is similar to the technology used for example to look at photographs on Google Photos or Image Search or Facebook or to recognise faces in the photos
Despite The fact that the application of AI in spotting eye diseases is currently very much a research project, there is growing optimism that it will soon be able to “grade” eye scans more effectively and certainly much more quickly and more cheaply than a human. Mass adoption of OCT which is supported by AI within opticians may well be only 3 years away – people will be able to walk into a high-street optician, have an OCT scan and have it graded by an AI system.
However, although machine learning will become an invaluable tool in early diagnosis and the planning of treatment, the advent of AI in handling so many patient data sets will require greater ethical scrutiny and appropriate governance. It is this data that gives machine learning its formidable power, and the NHS is in a unique position to offer huge, well-labelled datasets.
Also, questions such as how patient information which is so key to the use of AI is shared, who gets to use it and who gets to profit from it are questions that could fail to be properly answered in the rush to implement this important new technology. These questions will need to be answered as AI will soon be impacting on healthcare generally – for example, the hospital environment is such an expensive and complex system and clearly the humans working in it are simply overwhelmed by the scale and complexity of managing so many patients who are on so many different pathways and who need so many different tests and interventions. It becomes a massive co-ordination exercise and therefore AI can be applied so tasks in various areas of the hospital could be more efficiently and speedily prioritized to improve patient outcomes and care.
3.5 Re-thinking the eye test for nystagmus patients
Professor Jonathan T. Erichsen
Director of Postgraduate Research
Dr Matt J Dunn
Cardiff (Research Unit for Nystagmus – RUN) University
Dr Lee McIlreavy
Cardiff (Research Unit for Nystagmus – RUN) University
The Research Unit for Nystagmus [RUN] was established in the School of Optometry and Vision Sciences at Cardiff University over 10 years ago. Today, RUN remains the only such centre in Wales and has become one of the leading nystagmus research groups in the UK and worldwide.
Infantile nystagmus is a continuous oscillation of the eyes that arises shortly after birth and continues for life. Based in their three state-of-the-art laboratories, the research that Professor Jonathan Erichsen and his team are conducting into nystagmus highlights the critical need for eye tracking technology to provide high quality recordings of the eye movements to look for the characteristic oscillation pattern, deliver an accurate assessment of the impact of current and future treatments, and offer more suitable measurements of the improvement (if at all) in a person’s vision.
People with nystagmus generally perceive the world around them as stable, despite the continuous wobble of their eyes. Moreover, the “intensity” of the nystagmus, which can involve both the size and frequency of the eye oscillations, varies considerably in people depending on where they are looking (e.g. being at a minimum in their ‘null zone’) or on their emotional state (e.g. stress level).
In their quest to determine the underlying cause of infantile nystagmus and help develop treatments for the condition, they need to be able to measure, in real time, the eye movements in a variety of situations. Technological improvements (including large display screens and three-dimensional projection for binocular investigation) now allow them to record accurately and non-invasively the nystagmus oscillations as well as other eye movements made in response to different visual scenes or stimuli. This enables them to investigate the interaction between moment-to-moment eye movements and visual perception.
Supported by a cohort of over 100 volunteers with infantile nystagmus, Jonathan Erichsen and his team have challenged the conventional wisdom that currently available treatments (involving surgery and/or medication), which slow the nystagmus oscillations, will necessarily result in an improvement in vision. Indeed, they have discovered that visual acuity is largely unaffected by even quite large changes in his or her nystagmus. Whether under stress or using the nystagmus null zone, the result is still the same. It seems that any slowing of the movements is unlikely to produce much improvement in visual acuity. Nonetheless, people with nystagmus do sometimes report that they can “see better” and most will choose to look in a particular direction (i.e. use their null zone), which slows their eye movements, even if this means they need to adopt an unusual head posture. All of this suggests that their eye movements do affect some aspect of their vision.
Most recently, they have investigated whether nystagmus can have an effect on how long it takes to see something. Findings indicate that people with nystagmus do not take longer to mentally process visual information. However, there is evidence that due to the eye movements, people with nystagmus may need to look at things for longer than others to achieve their ‘best’ level of vision (i.e. their maximum visual acuity). How long it takes to find and/or discriminate objects or even people in different settings may have a profound impact on peoples’ everyday lives, so the team are now developing new tests that might better reflect how vision is affected by changes in nystagmus eye movements.
So, bearing in mind that the size and frequency of someone’s eye oscillations can vary depending on where they are looking and/or their degree of stress, the standard optometrist’s chart, which only tests the smallest letters that can be seen (i.e. visual acuity), is unlikely to be sufficient.
3.6 Amyloid beta as an early indicator of retinal disease and a potential biomarker for AMD
Dr J. Arjuna Ratnayaka
Clinical and Experimental Sciences,
Faculty of Medicine,
University of Southampton,
Age related macular degeneration (AMD) is a complex degenerative disorder causing irreversible loss of central vision. The underlying pathology of AMD is poorly understood, but impairment of the Retinal Pigment Epithelium (RPE) is considered to be of critical importance to disease onset and progression
Amyloid-beta (Ab) is produced by cleavage of the amyloid precursor protein (APP), which continuously occurs in all healthy individuals, resulting in a heterogeneous mixture of peptides with different solubility, stability and biological properties. However, Ab can be highly toxic and aggregate both intra and extracellularly, and also known to elicit inflammation. Furthermore, A accumulation in the brain is linked with neurodegeneration
Dr Arjuna Ratnayaka and his team have previously demonstrated that Ab is internalised in neurons and is trapped in lysosomes3. Recent findings support the emerging idea that Ab plays a crucial yet previously uncharacterised role in potentiating RPE degeneration in the ageing retina. Although Ab levels are abundantly present in vitreous fluid, levels increase with advancing age and can form deposits in photoreceptor outer segments (POS) In some AMD patients, Ab forms the core of sub-RPE deposits known as drusen, a key indicator of disease susceptibility. Hence, examination of human donor eyes linked Ab cores in drusen with advanced stages of AMD.
It is worth noting that Ab was found only in drusen from patients with AMD, but not in drusen from normal retinas. Ultrastructural analysis of drusen revealed 2-15μm sized spheres referred to as “amyloid vesicles”permeated with Ab and accounting for a significant proportion of the total drusen volume. It is thought that smaller clumps of Ab form initially interact with complement proteins/lipids in drusen to form a range of Ab structures reported in amyloid vesicles. The discovery of multiple reservoirs of A in the ageing retina has thus opened up new possibilities to understanding this complex degenerative disorder.
Ab could be used as a biomarker to predict AMD. Recent advances in OCT and other imaging technologies mean that retinal Ab levels could be non-invasively measured in patients. We may therefore be able to detect incipient pathology long before the onset of any disease. This idea was recently extended to measure Ab levels in the blood of AMD patients, which revealed that elevated Ab levels and ratios of Ab species in plasma were correlated with advanced AMD, particularly with the vascular form of the disease.
Our studies using ex-vivo and animal models as well as donor tissues correlate the importance of this potentially powerful biomarker and trigger of disease between cellular pathology and clinical applications.
3.7 Correcting mitochondrial decline and improving retinal function – implications for AMD as it reduces inflammation
Professor Glen Jeffery
Professor of Neuroscience
Inst Ophthalmology – Visual Neuroscience
Institute of Ophthalmology
Faculty of Brain Sciences
There is a growing body of evidence that the pace of aging is linked to metabolic rate, with high rates associated with faster aging (Speakman, 2005; Wang et al., 2010). Indeed, the retina is a key example of this as photoreceptors have the greatest energy demand in the body (Linsenmeier and Padnick-Silver, 2000). Experiments with mice have shown that mitochondria decline with age (Kokkinopoulos et al., 2013) and ATP the key sauce of cellular energy that they produce declines significantly by 3-4 months. Following these events, chronic inflammation becomes established (Catchpole et al., 2013; Hoh Kam et al., 2013; Xu et al., 2009), and retinal function declines (Kolesnikov et al., 2010; Li et al., 2001). It has been shown that there is a resulting 30% photoreceptor loss in both mouse and man (Cunea and Jeffery, 2007; Cunea et al., 2014; Curcio, 2001).
Supported by this recent body of research evidence, Professor Glen Jeffery and his team are showing that some of these features in the ageing retina can be corrected, based on the principle that specific long wave- lengths of light absorbed by cytochrome c oxidase (Fitzgerald et al., 2013), which is a key element in mitochondrial provision of ATP.
Experiments with mice expose to long wavelength light (670nm) have shown that retinal inflammation is reduced and retinal function improved by around 25% when the physiological function of the mouse eye is examined. The mitochondrial membranes recharge and more ATP is available for cellular function. So, Glen Jeffery’s data suggest, 670 nm light can significantly improve aged retinal function, perhaps by providing additional ATP for the energy demanding cellular pumps that all neuronal cells have and this extra energy is associated with a reduction in the chronic level of inflammation that the ageing retina suffers from. This relatively simple therapeutic route may have significant implications for the preventative treatment of early AMD prior to the onset of dry AMD (geographic atrophy) and retinal aging.
Perhaps as importantly, Glen Jeffery’s laboratory has been able to monitor mitochondrial function in the living eye via reflected light (Kaynezhad et al 2016) and consequently they may be able to identify those in which the function is being undermined at a relatively rapid rate, and as such be vulnerable to disease.
Glen Jeffery’s research is supported by the Biotechnological and Biological Research Council UK.
3.8 The flexibility of OCT and the accommodation of under represented groups
Dr Denize Atan
BM BCh MA MRCP FRCOphth PGC Med Ed PhD
SOCS Lead for Women in Science
Consultant Senior Lecturer in Ophthalmology
School of Clinical Sciences
F38, Biomedical Sciences Building
University of Bristol
Optical coherent tomography (OCT) has revolutionized ophthalmic practice because we are now able to detect and monitor disease affecting the cornea and retina more objectively.
– Better detection techniques = earlier diagnosis and treatment
– Better monitoring techniques = clearer guidelines about when to intervene or not, based on objective measurements (rather than drawings or photographs)
The best example is how OCT has changed the management of age-related macular degeneration. The decision about when to treat and how often with intravitreal anti-VEGF agents is now almost entirely based on the results of OCT imaging.
The number of applications for OCT is ever expanding so that we can now measure vitreous inflammation, for example, to monitor disease activity in uveitis.
Under-represented groups in previous research using OCT are young children and patients with physical disabilities because standard OCT machines require the subject to sit up at the machine and place their chin on a rest – neonates, young children and physically disabled individuals cannot do this.
Research from Irene Gottlob in Leicester has shown that the retina is still developing in young infants after birth. This was not known before because the technology was not available to image neonates with OCT previously, but now there is an OCT machine (Bioptigen) with a portable imaging probe that makes this possible. Drs Denize Atan and Cathy Williams in Bristol are collaborating with Irene Gottlob to collect further normative data about the normal postnatal development of the retina with funding from Fight for Sight and the same Bioptigen OCT machine. The only other centre in the UK with a Bioptigen machine is Moorfields Eye Hospital.
It is very important to collect normative data so that we can recognize true pathology as opposed to the changes that normally occur during postnatal retinal development. We can then diagnose early onset/congenital retinal diseases, for example, albinism. Albinism can be difficult to diagnose at an early age because the tests that are commonly used rely on some degree of patient cooperation – otherwise the results are not reliable. This means that the tests are often repeated again and again until they give more reliable results when the patient is older. The portable OCT helps to make the diagnosis at a very young age as it is less reliant on patient cooperation and can be performed on subjects who are lying down or unable to sit at a normal OCT machine. This means that new treatment modalities like gene therapy or l-dopa for albinism can be given earlier – even as the retina is continuing to develop – to preserve vision.
There are other advances in imaging technology, currently only available in the research environment, for example, to image individual photoreceptors – rods and cones. This will allow early diagnosis of photoreceptor degeneration before other more invasive tests are performed, e.g. visual electrophysiology, or those that rely on patient cooperation (problematic in young children) and would allow more targeted genetic testing.
3.9 Imaging – a powerful illustration of innovation
Director – Visionbridge
Patients are quite rightly continuing to ask how eye research can better predict, detect, diagnose and monitor eye disease – and indeed ultimately restore sight. The answers can be found in the fast moving world of Imaging.
Tremendous innovation is taking place across the wide range of eye research activities but it is clearer than an intraocular lens that the real catalyst which will deliver the maximum potential for positive patient outcomes and most notably and critically influence if not determine the direction of travel for the greatest number of research activities further downstream is Imaging
Imaging is beginning to make a noticeable impact on positive surgical outcomes by assisting ophthalmic surgeons in better understanding the context in which they are operating, provide greater accuracy in the delivery of treatments and pinpoint the areas of greater or lesser risk prior to invasive surgery – and this is all being achieved with optical coherence tomography (OCT) in support of Robotics.
We are always told that “being forewarned is forearmed” and this is beautifully illustrated in the extraordinary advances in detection – for example, Adaptive Optics (AO) is allowing clinicians to view biomarkers of disease in the form of damaged tissue structures, toxic proteins, inflammation and debris as well as individual cellular abnormalities and dysfunction. Following closely behind, the molecular level will soon be reached thus creating even clearer predictors of impending eye disease by revealing even more detail about for example individual cell metabolisms, cortical remodelling and adaptation to retinal degeneration and even cell death (senescence). And let’s not forget the role that Imaging could play in detecting the early onset of Alzheimer’s and Parkinsons and indeed in spotting other diseases such as diabetes and diabetic neuropathy, high blood pressure, meningitis, brain tumours and malaria which can all impact on sight if not treated early.
Improved detection can therefore enhance clinicians’ ability to predict the likelihood of eye disease and so determine the need for early medical intervention, identify the most appropriate type of treatment if required and assist patients in planning for the future and making more informed lifestyle choices accordingly. Surely, parents of young children could be greatly helped by improved less invasive imaging devices that can spot abnormal microscopic structures in the retina or gauge the density of photoreceptors and indeed older patients would be hugely reassured if there was a surefire technique for predicting the chance of dry macular degeneration progressing to the wet form?
Imaging can also ride to the rescue in the form of improved monitoring of eye disease too. The secondary sector’s ability to cope with the increasing demands and numbers of patients could be greatly enhanced if advanced imaging techniques and equipment were widely adopted by practitioners in the primary sector – indeed, numbers of referrals that currently do not subsequently require an ophthalmological appointment could be drastically cut and patients with stabilised conditions and in post surgical phases could be well supported by an upskilled workforce of optometrists.
Peering even further over the horizon, the degrees of predictability drawn from Imaging could be greatly enhanced by an emerging and powerful ally in the form of Artificial Intelligence (AI). If patients are to receive meaningful and timely treatments then human error during image analysis must be minimised, speed of analysis accelerated and indeed correlations and patterns amongst images that perhaps clinicians have not even thought about need to be examined. So AI in the form of DeepMind’s so called “Machine Learning” should be deployed to facilitate in reaching such goals.
As Mr Pearse Keane (NIHR Clinician Scientist and Honorary Consultant Ophthalmologist, NIHR Biomedical Research Centre, Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology), a strong supporter of VisionBridge noted:
“Advances in ocular imaging will be fundamental to all aspects of vision research, and are likely to drive many breakthroughs in eye disease diagnosis and treatment in the next decade. These advances will allow visualisation of every cell type within the eye, from cellular ultrastructure to underlying molecular processes. In parallel, advances in machine learning and artificial intelligence will allow clinicians and scientists to improve patient care and derive new insights into disease pathophysiology. Taken together, new imaging hardware and new artificial intelligence techniques are likely to reinvent the eye examination for the 21st Century.”
There is no doubt that the eye which is such an indescribably complex and infinitely adaptable organ is under attack on a daily basis from mutant genes, injury, auto-immune responses, infection, lifestyle choices and the ageing process. So, further and faster developments in the hardware and software within Imaging will constitute the most effective shield against such attacks in both the developing and developed countries but a $1bn injection would help to sustain and secure such exciting progress.
3.10 An innovative testing and monitoring regime yielding results
Professor David Crabb
Professor of Statistics and Vision Research
City University London
Vision loss from glaucoma occurs when the optic nerve is damaged. In most cases, increased pressure inside the eye (intraocular pressure), is thought to contribute to this damage.
With this in mind, despite the fact that Medication such as “Prostaglandin analog” eye drops (the most commonly prescribed treatment for glaucoma) to lower raised eye pressure has been used for decades as the main treatment for open angle glaucoma (OAG) to delay progressive vision loss, it had not been proved that this drug had a measurable impact on reducing the risk of further sight loss.
So, David Crabb, co-author and Professor of Statistics and Vision Research at City University London, helped design the innovative testing and monitoring regime used in the trial which epitomized the collaborative clinical working that is so important and which again highlighted glaucoma research in the UK as world leading.
Glaucoma is normally a slow acting disease and observation periods in trials are long. Therefore, David Crabb and his team shortened the trial with the novel use of more frequent testing of patient’s vision and the use of precise statistical tests. The trial has set a new benchmark for speeding up novel drug development, reducing costs of trials and increasing the likelihood of bringing new drugs to patients.
The study found that the risk of visual deterioration was over 50% lower in the group treated with daily pressure-lowering eye drops compared to those using placebo drops over 2 years. Importantly, because of the trial design, a significant difference in treatment effects could be seen between the groups after just 12 months.
3.11 Translation of Ophthalmic Technology to Enhance Patient’s Vision
Professor James Wolffsohn
Deputy Executive Dean, Aston University
With a rapidly ageing population, the demands on GP’s and hospitals from ocular disease have become overwhelming. Eye disease prevalence increases with age, as with most organs, and innovative treatments, such as for the wet form of age-related macular degeneration, is consuming much more time of our relatively small number of ophthalmologists.
So Professor James Wolffsohn’s collaborative and multi-disciplinary team at Aston University is focusing on low cost, portable, objective instrumentation using artificial intelligence to aid in the diagnosis and evidence-based management of patient in primary care. Projects include: advanced, ‘intelligent’, diagnostic support software; portable, low cost, innovative instrumentation to assess eye health and to refract the eyes; and refinement and validation of eye tracking equipment to diagnose and manage visual fatigue.
For example, traditional solutions in the optical industry don’t translate to markets where the clinic needs to travel to the client rather than the client to the clinic. Large expensive white instruments are being replaced, allowing the number of referrals to secondary care to be reduced (and to be dealt with more efficiently such as through telemedicine), while improving the vision and visual comfort of patients through advancements in contact lenses and intraocular lenses implanted as part of cataract surgery.
3.12 A collaborative approach to improve visual field tests
Professor Paul H. Artes
Professor of Eye and Vision Sciences, School of Health Professions, Plymouth University
Professor Paul Artes and his team in Plymouth focus on creating better visual field tests for patients with advanced glaucoma. These patients often have only a small part of remaining central vision that they use to read, recognize faces, and watch television. Much of the surrounding field of vision is irretrievably damaged, and the important area of “indirect” vision that healthy people use subconsciously to move about is no longer available. Sometimes, small “islands” can remain in the far periphery, and it is important that patients are treated as well as possible to preserve these areas.
Current visual field tests do not measure peripheral vision well enough, and they also do not work well for the most important central areas of vision when there is substantial damage. Most patients with advanced damage find visual field tests difficult and frustrating. The results can vary a great deal between one examination and the next, and this means that clinicians often have little confidence in making decisions of whether the patients’ treatment is adequate or not.
Against this background, Professor Artes and his team aim to create tests that are easier to perform for patients and provide more reliable information to eye health professionals. If successful, these new tests will lead to better treatment of individual patients but they will also speed up progress with comparing drugs and surgical techniques. Ultimately, they will improve understanding of how eye diseases and their treatments affect patients’ “real-world” visual function – their ability to move through a busy environment, climb stairs or drive a car.
His approach to this field of “clinical vision research” is to break down individual challenges into smaller pieces and try to find solutions accordingly and then translate the specific problem into the language spoken within other disciplines such as vision science, mathematics, or computer science. Step two is to translate the challenge into a practical clinical application that can be used by eye doctors in the consulting room, for example a new vision test or a computer programme that helps doctors to make better sense of data from existing tests. However sometimes he will work with basic scientists from his field or from other disciplines to understand the underlying problem, formulate the right research question and design the experiments required to solve it.
Paul is a founding member of the “Open Perimetry Initiative”, a group of scientists, engineers, and doctors who collaborate on making high-end commercial equipment accessible for scientific studies, and it is notable that his groups’ work on improving visual field tests relies on close collaboration with industrial partners such as instrument manufacturers.
This group freely share tools and expertise, and this has tremendously accelerated progress in terms of translating new scientific knowledge into prototype clinical tests. In turn, instrument companies are beginning to benefit from a much wider network of scientists for research and development than was available in the past – a development that will lead to more rapid advances in clinical tools and, ultimately, clinical care.
Bearing in mind the many unsolved problems in eye care and the new potential solutions which are becoming increasingly available through advances in basic science laboratories, Paul Artes is passionate about the education and training of new scientists (PhD students and postdoctoral research fellows) to ensure that his fields of research continue to make sense of these findings and bridge the gap between bench and bedside.
3.13 The importance and translational benefits of improving the accuracy of diagnostic tests
Dr Tony Remond
Senior Lecturer & Deputy Director of Postgraduate Research
School of Optometry and Vision Sciences
Damage to the visual field is the primary functional biomarker for glaucoma, the second leading cause of blindness globally, and is screened for by clinicians with perimetry, a clinically-adapted psychophysical technique that uses spots of light varying in brightness to probe the visual pathway. It is well understood that earlier detection followed by appropriate treatment, of glaucoma are essential for a better visual prognosis. However, current clinical methods for measuring visual field damage are inefficient for detecting the earliest stages of glaucoma and its progression, and more appropriate stimuli are urgently needed to improve the diagnostic accuracy of perimetry. It is only through rigorous psychophysical research that regions of the visual pathway and levels of sight affected in glaucoma can be identified and then develop an understanding of how precisely these changes can be detected clinically at the earliest opportunity.
With this in mind, by studying how the visual system processes and behaves in response to visual stimuli, including spots of light, detailed patterns, or natural scenes, Dr Tony Redmond and his team who have made significant progress in the development and optimization of efficient clinical tests for glaucoma, continue to probe various regions of the visual pathway, from the eye to the brain, that are responsible for different levels of sight. This area of “visual psychophysics” helps them better understand how the functional architecture of these structures enables us to see and perceive everyday scenes, as well as how various attributes of sight are affected in disease.
So, armed with an understanding of these mechanisms in health and disease, a substantial translational arm of Tony Redmond’s research is aimed at developing optimum stimuli for identifying disease from normal eye and brain function in the clinical setting.
More recently, in collaboration with colleagues at the Cardiff University Brain Research Imaging Centre (CUBRIC), psychophysics has been combined with high-resolution neuroimaging (functional MRI) to more accurately underpin the regions of the visual pathway responsible for the earliest changes in vision in glaucoma. As a result, this will enable them to establish a clearer idea of how visual scenes appear to patients and to refine the development of the most accurate clinical test of early visual field damage.
3.14 Handheld Oximetric Ophthalmoscope for Enhanced Diagnosis of Retinopathy of Prematurity
Professor Andrew I McNaught
Honorary Professor at the School of Health Sciences, Plymouth University.
Consultant ophthalmologist – Cheltenham General Hospital
Retinopathy of prematurity (ROP) is a potentially blinding condition that can lead to retinal detachment and blindness in severely premature and underweight babies. It is associated with abnormal development of retinal blood vessels that may be classified as severity of ‘plus disease’ from a comparison of images of retinal blood vessels with reference characteristics. Early screening and diagnosis of plus disease and adaptation of treatment according to the severity are effective in reducing the development of ROP and preventing blindness. About 5-8% of premature babies develop ROP in developed countries such as the UK where good treatment for premature babies exists, but the incidence is about 30% in middle-income developing countries such as in Latin America and Asia where more premature babies are surviving, but screening for ROP is not as well developed.
Currently screening involves viewing the retina with an indirect ophthalmoscope whilst physically manipulating the eyeball and recording photographs of the retina using a specialised, but cumbersome and expensive ophthalmic camera called a Retcam (approx. £50k each) that is placed in physical contact with the eye and is stressful for the fragile premature baby and the parents and has to be repeated regularly during the first few weeks of life. In light of this, a research group at Oxford University, headed by Dr Rebeccah Slater and Mr CK Patel, is investigating how to measure the stress of ROP eye checks and treatment. The group will investigate how to improve on current techniques to make the process less stressful and painful as this is very important for the baby’s health and development.
Conventional practice dictates that the retinal photographs are studied by clinicians for abnormal shapes in the retinal veins and arteries indicative of plus disease and treatment of the baby is targeted based on the perceived, subjective development of the disease. Current research is developing computer programmes that promise to more objectively and reliably classify the severity of plus disease and improve the selection of the optimal treatment such as laser therapy or cryotherapy (freezing).
However, Professor McNaught in close collaboration with Professor Andy Harvey and colleagues (who built the ROP focused ophthalmoscope and are now developing the prototype at the Department of Physics and Astronomy, Glasgow University), aim to deliver a device that will improve the diagnosis of the ROP and hence reduce blindness in premature babies in the UK and abroad. This will not only use a new design and exploit low-cost consumer technology to produce a camera for a significantly reduced cost compared to a Retcam but it will accurately distinguish between veins and arteries to enhance automated and objective classification of ROP. It will also be non contact thus reducing stress to babies and handheld and highly mobile to greatly improve the usability of the instrument.
In the developed and developing worlds where ROP-specialists are seldom found outside major population centres, the features outlined above will reduce the skill level required to record images and this will be highly suited for use in telemedicine for classification of ROP.
3.15 A new way of detecting and monitoring eye disease
Professor David Crabb
Professor of Statistics and Vision Research
City University London
Eye movements are a continuous and ever-present part of vision. When we look around our eyes generate saccadic eye movements(extremely fast voluntary movement of the eyes, allowing them to accurately refix on an object in the visual field), interspersed by periods of time where the eyes are stable (fixations). Scan paths reveal the sequence of fixations and saccades. Scan path data, collected during the time a person is engaged in watching a film could give an individual ‘eye movement fingerprint’ akin to the level of data that might be found in a genetic profile. So Professor David Crabb and his team at City University have devised a “proof of principle” project to prove the concept that there is a signature or ‘fingerprint’ in people’s scanpaths and to accumulate evidence to show that patients with age-related visual disease have different eye movements compared to visually healthy people. Prof Crabb has already collected scan paths from 100 elderly people and will develop statistical methods to analyse these complex eye movement data. This will determine if the concept of monitoring eye movements in people while watching a film could reveal data that could be a biomarker for eye disease. This ‘proof of principle’ work could lead to ‘Eyecatcher’ potentially becoming a new way of detecting and monitoring eye disease.
3.16 Seeing what they see: Compensating for cortical visual dysfunction in Alzheimer’s disease
Dr. Keir Yong
Dementia Research Centre,
UCL Institute of Neurology, London
“Seeing what they see” is a project which draws together experts in neuropsychology, engineering and social science and individuals living with typical Alzheimer’s disease (AD) and atypical AD – namely, the syndrome posterior cortical atrophy (PCA) which primarily affects vision rather than memory. This project is designed to understand and address the issue of dementia-related visual impairment. Some of the broad motivations for the project were that visual impairment in dementia is under-recognised and poorly managed, and most previous research has focussed on people with dementia who also have coincident eyesight loss without addressing impairments of cortical vision (‘brainsight’) caused directly by conditions such as AD.
This project consists of various strands of work primarily emphasising different disciplines, with the overall aim to develop a better understanding of the nature of visual impairment arising due to AD and PCA, ultimately to develop simple aids and strategies to support everyday abilities. Investigations of dementia-related visual impairment to date have included studying its qualitative and quantitative impact, the significance of the environment, assessment of physical location, activity and eye movement patterns, and detailed exploration of specific visual symptoms and their anatomical basis. The project team have also contributed advances in methodology including the development of new tests for more reliable visual assessment and novel experiments for assessing navigation and object finding. Our initial findings outline which perceptual conditions are optimal for patients with cortical visual dysfunction to identify simple stimuli, as well as carry out more complex activities such as reading or navigation.
These findings have provided the basis for a computer-based intervention intended to minimise reading problems experienced by individuals with PCA and steps have been taken to address ‘appropriate methods of visual assessment’, identified as the top priority after consultation with patients, carers, researchers and health professionals. Collaboration has also taken place with the College of Optometrists and a range of optometrists through workshops, conferences and interest groups (e.g. Dementia and Sight Loss interest group).
3.17 Enhancing glaucoma detection with a novel technique to image and track individual retinal cell death
Edited by Julian Jackson
Director – Visionbridge
The processes of neurodegeneration are implicated in several degenerative diseases of the retina. These include glaucoma, age-related macular degeneration and some inherited retinal disorders.
Professor M Francesca Cordeiro and her Glaucoma and Retinal Neurodegenerative Disease Research Group focuseson mechanisms of neurodegeneration and vision loss, particularly related to the early diagnosis and management of age-related neurodegenerative processes.
The key aims of her group are as follows:
- Identify early markers of cell processes in neurodegenerative disease in the eye – including Glaucoma, Alzheimer’s, Parkinson’s Diseases
- Establish new methods of early diagnosis and treatment of these diseases – using the eye as a window on to the brain
- Develop non-invasive screening and monitoring of neurodegeneration
- Investigate Neuroprotection and rescue modalities
- Assess novel delivery methods of diagnostic and therapeutic agents – in the eye and in the brain
These are to be achieved using novel non-invasive techniques to assess structural and functional changes in different models of disease and their treatment, with a view to offering quick and effective translation to the clinical arena.
A strong emphasis in Professor Cordeiro’s work has been to make use of the strong expertise at UCL to encourage a multidisciplinary approach in her research. She greatly values strong and successful collaborations with a range of experts at UCL, Imperial and externally too.
One particular (first) clinical trial supported by such collaboration is the so called “detection of apoptosing retinal cells” (DARC) project. It is not only another shining example of the possible translational benefits of eye research but also how painstaking research can greatly improve the chances of earlier detection of glaucoma (the world’s leading cause of irreversible blindness), by spotting individual nerve cell death much earlier than it has been possible hitherto, thus allowing for enhanced diagnosis and an earlier, more refined therapeutic interventions in the disease process to preserve remaining vision.
To underline this point, Detecting glaucoma early is vital as symptoms are not always obvious. Although detection has been improving, most patients have lost a third of vision by the time they are diagnosed because conventional clinical tests cannot detect abnormalities until extensive RGC death and significant vision loss have already occurred.
The “DARC” technique uses a specially developed fluorescent marker which attaches to cell proteins when injected into patients. Sick cells appear as white fluorescent spots during eye examination. The equipment used is similar to that available during routine hospital eye examinations. Researchers hope that eventually it may be possible for opticians to do the tests, enabling even earlier detection of the disease.
Initial clinical trials were carried out on a small number of glaucoma patients and compared with tests on healthy people. The initial clinical trials established the safety of the test for patients.
The test also has potential for early diagnosis of other degenerative neurological conditions, including Parkinson’s, Alzheimer’s and multiple sclerosis.
Eye research constantly questions the efficacy of standard treatment approaches as it remains clear that not all treatments suit every patient and indeed there is always an imperative to create treatments which are better targeted, less invasive, longer lasting and require less applications in the fight to prevent further sight loss, stabilise conditions and ultimately restore sight. Work is also ongoing to treat patients without the current unpleasant side effects and surgical shortcomings. The breadth and depth of eye research continues to grow in the treatment arena, reflected in the research into stem cell and gene therapies, drug treatments and drug delivery, pharmacogenetics and personalised medicine, light, x-ray and other non invasive therapies, antibodies, neuro-protection, the innovation behind surgical instruments and techniques that are safer, faster, more accurate and less invasive.
4.1 New corneal therapies: From Bench to Bedside
Professor Keith Meek
Professor and Chair of Structural Biophysics Research Group
College of Biomedical and Life Sciences School of Optometry and Vision Sciences
All clinical treatments are underpinned by basic scientific research, sometimes retrospectively, but mostly by forward planning and development, and the UK has historically been at the forefront of such efforts.
Indeed, the Structural Biophysics Group at Cardiff University led by Professor Keith Meek highlights the benefits of high levels of specialisation and multi-disciplinary working in determining positive clinical outcomes for patients.
Patients at high risk of corneal blindness face the twin challenges of possible corneal rejection following a corneal transplant and the worldwide shortage of donated corneas. So, notwithstanding the ongoing stem cell research which is providing some hope (although only really viable in developed nations as cell expansion costs that meet regulatory requirements are too high), it is important to drive towards the removal of the reliance on donor corneal transplantation.
So, specific research initiatives are focusing on developing and successfully testing cell-free, pro-regeneration implants comprising genetically produced human collagen (Collagen is a hard, insoluble and fibrous protein that makes up one-third of the protein in the human body) as safe, reliable alternatives to human donor transplants in a range of high-risk corneal transplantation patients. a completely synthetic collagen mimetic (a material imitating collagen) has been developed to treat corneal diseases. Successful testing in a simple organ system like the cornea will in future allow for the extension to more complex applications such as skin and cardiac regeneration.
This method may also be applied eventually to “Corneal crosslinking”, which is now widely used to treat progressive keratoconus and other conditions. However, the conventional treatment is uncomfortable, and takes over 30 minutes, leaving patients vulnerable to infection. Quicker, pain-free methods are being developed in the Cardiff laboratory (including the St Thomas’/Cardiff iontophoresis protocol) that could translate into clinical practice within a few years.
Also, the biophysical and biomechanical methods that Professor Keith Meek and his team have developed to study the cornea have applications elsewhere in the eye. For example, plaque brachytherapy is used to treat ocular cancers within the eyeball. A radioactive plaque is placed externally on the white sclera and radiation passes through the eyeball into the eye to kill the cancer cells. However, the extent to which the radiation destroys the scleral tissue is unknown, so removal of the eye is the usual option if the initial therapy fails. Basic studies are being carried out to measure the changes in the irradiated sclera with the longer term aim of strengthening the sclera to make it more resistant to radiation damage and thus permit secondary irradiation if necessary, rather than removal of the eye.
4.2 An alternative way to manage glaucoma
Dr Craig Boote
School of Optometry and Vision Sciences
Glaucoma is a leading cause of vision impairment and blindness in the UK. It is linked to pressure changes inside the eye, which can permanently damage the retinal cell connections that form the optic nerve – the visual information pathway from eye to brain. Damage from fluctuations in eye pressure is transmitted to the optic nerve head via the sclera – the white of the eye. Scientists at Cardiff University have been using powerful x-ray and microscope technologies to study the connective tissue protein collagen in the sclera under high-pressure conditions. They have discovered that, as eye pressure increases, collagen in the sclera reorganises in a way that could make optic nerve damage more likely. The team also found that a person’s age and whether or not they have diabetes are also important factors in this degenerative process because they affect the overall rigidity of the eyeball. According to the study’s principal investigator, Dr Craig Boote:
These are important findings as they could open up new approaches for treating glaucoma. There are many individuals who do not respond to the standard treatment approach of lowering eye pressure, but by changing the mechanics of the sclera, for example by using collagen “cross-linking” (a procedure that encourages the formation of chemical bonds between adjacent collagen strands – like the rungs on a ladder) to strengthen specific regions of the tissue, it could be possible to shield the optic nerve from pressure-induced damage. Similar approaches are already being used successfully in the clinic, for example as a corneal treatment for keratoconus patients.”
4.3 Robotics for Eye Surgery: Improving Surgical Dexterity and Speed
Dr Christos Bergeles
Lecturer, Department of Medical Physics and Biomedical Engineering of University College London.
Translational Imaging Group
Centre for Medical Image Computing
The benefits that Robotics are bringing to Healthcare are self-evident. From efficient and rapid delivery of food and medicine from one hospital wing to another, to supporting the work of nurses and physicians in patient rehabilitation, and assisting in surgery by providing increased dexterity, robotics are becoming a key pillar of efficient and effective healthcare services.
Following their increased uptake in the domains of rehabilitation, laparoscopic or keyhole surgery (which ensures less time in hospital and faster recovery times) and orthopaedics (prevention/treatment of skeletal and associated muscle/bone disorders), , robotics is starting to find applications in eye surgery, fulfilling the unique needs of this niche area of healthcare.
Two main research branches can be identified in robotics for eye surgery. For example:
Firstly, robotics aim to speed up and simplify existing operations of high volume such as cataract surgery, corneal sculpting and transplantation where various procedures can be supported by snake like robotic instrumentation in the front (anterior) of the eye. Also, in the back (posterior) of the eye, robots aim to improve the precision of epiretinal membrane peeling and increase the safety of the procedure by providing auditory, visual, and haptic (touch) feedback to the surgeon when risks are identified.
Secondly, research is being conducted to create systems that surpass the surgeon’s capabilities towards enabling currently impossible interventions. Most notably, researchers are investigating the delivery of stem cells, genes, and small drug molecules to specific retinal layers. Therefore, with those new systems, it will be possible to reach and affect every part of the retinal surface, from the photoreceptors to the retinal pigment epithelium and choroid.
However, despite the increasing success of robots in improving speed, safety and the minimally invasive nature of existing surgical procedures, they all need to achieve very high levels of precision, meeting the minimum requirement of suppressing/removing the natural hand tremor, especially if subretinal interventions are to be considered. Also, As the forces applied in eye surgery are sometimes below the threshold of human perception, the recording and amplification of haptic information is vitally important, thereby keeping the clinician in the loop and in control of the robot.
Close collaboration between engineers and clinicians is ensuring that robots continue to be developed which are clinically relevant and allow for co-manipulation and full hands on control by the clinician. In time, robotic tools and systems will become an integral and indispensable part of the operating theatre.
4.4 A novel drug treatment under clinical trial
Professor Andrew Lotery
Professor of Ophthalmology, director Clinical Services Research Group
University Hospital Southampton
A novel drug treatment “Lampalizumab” may well be the answer for some of those patients with the advanced form of macular degeneration or “dry” AMD also known as “Geographic Atrophy” (GA). It is designed to target the complement genes and suppress the overactive complement defence system, which can lead to inflammation and associated tissue and cellular damage. However it might simply slow down the progression of GA rather than improve vision.
This novel treatment injected into the eye is currently being tested in a Roche sponsored Phase 3 clinical trial supervised by Roche Chief Investigator Professor Andrew Lotery and his team in Southampton University and this work could lead to personalised treatments that are based on individual patient’s genetic tests. *results from the phase 3 clinical trial of lampalizumab are expected by end of 2017.
4.5 Model eyes that enhance the safety and efficacy of surgical training
Mr John Ferris
Gloucestershire Royal Hospital
Stroud General Hospital
Cheltenham General Hospital
Surgical opportunities for trainees are continually being reduced as a result of shorter training programmes, fewer surgical opportunities on operating lists which are filled to capacity and a greater emphasis on improving the safety of surgical training. This is a far cry from the long training programmes, virtually unlimited access to surgical cases and a “see one do one teach one” attitude that prevailed years ago.
Against this backdrop, The Simulated Ocular Surgery (SOS) model eyes have been refined over a 15 year period by Phillips Studios, using a variety of materials that accurately replicate the look and more importantly the feel of real ocular tissues. They come complete with conjunctiva, Tenons capsule, extraocular muscles, including superior and inferior oblique’s and a sclera that handles just like a human eye. The cataract models have a life like capsule , nuclei of varying densities and a posterior chamber that can be filled with a vitreous like material . The retinal eyes can be used to perform vitrectomies, have retinal tears and membranes that can be peeled. Furthermore the model heads have noses and eyebrows that will hamper surgical manoeuvres just as they do in real life.
There are over 20 types of model eyes, each one being custom made to faithfully replicate the simulation of a particular operation. In the field of glaucoma surgery there are eyes designed for practicing trabeculectomy (surgical partial removal of eye’s drainage system to reduce internal ocular pressure), Ahmed and Baerveldt valve surgery and for the insertion of a wide range of Micro-Invasive Glaucoma Surgery (MIGS) devices. All of these procedures can be practiced outside of the operating theatre, using bench-top microscopes. It is also possible to practice managing uncommon surgical complications, much in the same way as pilots practice dealing with mechanical failures and other untoward events.
The use of the SOS system has now been integrated into training in the UK and is becoming more widespread in the US. Recently Orbis, the flying eye hospital charity, has incorporated the system into their training programmes in Indonesia, China and South America.
These simulation techniques can be seen on the Simulated Ocular Surgery website www.simulatedocularsurgery.com
There is no doubt that sustained deliberate practice speeds up the learning curve, enabling trainees to reach a high level of competence before they perform live surgery for the first time. This results in a more comfortable learning experience and a more rapid progression to becoming an adept adaptable surgeon, whilst also making surgical training safer for patients. Another byproduct of this enhanced training program is that operations are performed in a more timely fashion, so improving theatre throughput and enabling more cases to be performed on each operating list.
4.6 Bioengineering – the ability to rethink models of treatment and care
a.) Development of a less invasive therapy for Keratoconus with potentially radical effects on the delivery of patient care
Professor Rachel Williams
Professor of Ophthalmic Bioengineering
Department of Eye and Vision Science University of Liverpool | William Duncan Building | 6 West Derby Street | Liverpool | L7 8TX
Professor Colin Willoughby
Professor of Molecular Ophthalmology
Institute of Ageing and Chronic Disease
University of Liverpool
Keratoconus is a progressive corneal thinning disorder that is a significant health burden in teenagers and work-age adults. Increasingly, a therapeutic procedure called “collagen cross-linking” using ultraviolet A (UVA) irradiation combined with the photosensitiser riboflavin has been used as a treatment for keratoconus to stiffen the cornea.
Current cross-linking requires exposure to UVA radiation which is toxic to the cornea and may result in long term damage. In light of this risk keratoconus patients must have a minimal corneal thickness or this treatment is not applicable and no other therapy can be used to stabilise their condition and thus they may eventually require a corneal transplant. There is also a need to remove the corneal epithelium to facilitate diffusion of riboflavin throughout the corneal stroma causing significant discomfort for the patient and an increased infection risk.
So Professor Rachel Williams and Professor Colin Willoughby in the Department of Eye and Vision Science at The University of Liverpool in partnership with the Aravind Eye Care System in Madurai (India) have developed an alternative therapeutic approach to conventional corneal cross-linking for keratoconus.
They have created a novel chemical cross-linker to cause corneal cross-linking without the need to remove the epithelium or the use of UVA irradiation therefore avoiding the need to withhold treatment on the basis of thickness. The novel chemical cross-linker has been extensively tested in the laboratory and been shown to increase the stiffness of ex vivo pig cornea by 85% and this increase in mechanical properties was related to chemical changes in the tissue. Also, her team has shown there is no cytotoxicity (for example arising from mechanical or chemical trauma or abuse of toxic eye drops) to corneal epithelial and endothelial cell in culture.
This treatment can be administered as a simple eye drop removing the need for specialised equipment in a hospital setting – indeed, the less invasive nature of this therapy, the resulting reduced risk of collateral damage and the fact that it can be administered away from a hospital setting might have a major impact on the clinical treatment of these patients.
b.) Novel ways of fighting infection, delivering drugs and post operative therapies
Professor of Ophthalmic Bioengineering
Department of Eye and Vision Science
University of Liverpool
Professor Stephen Kaye
Professor of Ophthalmology
Lead for the Corneal Service at The Royal Liverpool University Hospital
The cornea is the clear window at the front of the eye. Following surgery or various treatments to the cornea a bandage contact lens (BCL) will frequently be used to protect the cornea and increase comfort for the patient. To reduce the risk of infection antibiotics will also normally be administered. We have developed a novel hydrogel with a high water content, excellent transparency and that has mechanical properties similar to existing hydrogel contact lenses. The specific advantage of this new hydrogel is that it is naturally antimicrobial unlike any of the existing contact lens materials and there is certainly potential for its use as an antimicrobial bandage contact lens post-surgery or intervention, such as corneal crosslinking. It could also increase comfort and reduce infection for patients.
The effective treatment of corneal infection relies on frequent application of antibiotic drops; routinely every 5-15 minutes for the first 48 hours, then 2-6 hourly over 1-2 weeks. Therefore, to circumvent such a drug delivery regime, Rachel Williams and her team have been developing BCLs that deliver therapeutic doses of antimicrobial drugs in a sustained and controlled manner which would provide a more effective treatment strategy and could augment conventional treatments. They have demonstrated that model antibiotics and model fungals can be incorporated into the new hydrogels and have antimicrobial properties in vitro.
Another example where the use of a contact lens material with intrinsic antimicrobial properties could greatly reduce the risk of infection by specifically inhibiting surface colonisation of the lens and subsequent microbial biofilm formation, is best seen in the fight against “Microbial keratitis” (MK). This is one of the commonest conditions affecting the cornea, accounting for 5% of cases of blindness worldwide. Contact lenses worn for vision are associated with a six fold increase in MK.
Longer term, the potential of the new hydrogel material could be optimised as a daily disposable contact lens.
These materials are being developed in the Department of Eye and Vision Science at The University of Liverpool in collaboration with SpheriTech Ltd.
4.7 Gene therapy options for AMD
Dr. Simon Clark
Centre for Ophthalmology & Vision Sciences
Faculty of Medicine and Human Sciences
University of Manchester
When compared to other therapy options, such as traditional drug based treatments, gene therapy is best suited at the early stages of disease, preferably prior to major physical changes. This can be achieved given the genetic nature of AMD and well developed algorithms that take into account a patients genes, diet, age and smoking to predict their level of risk. Other methods are best suited to later stage disease, such as stem cell therapies, that seek to replace the RPE cells already lost because of disease progression.
“Given the localised nature of AMD, gene therapy represents a very real opportunity to deliver therapeutic potential right in the part of the eye we here it is needed. Altering the way the retinal pigment epithelium (RPE) cells contribute to inflammation, lipid synthesis and blood vessel growth means a patient would have a therapy constantly maintained in their eye. This may be delivered by a single sub retinal injection, removing the need for monthly eye clinic appointments currently endured by patients receiving anti-VEGF.
While the anti-VEGF era has seen a tremendous advance in our approach to AMD, the window of opportunity for initiating this therapy is very short. In some senses, anti-VEGF therapy is palliative medicine. Patients are observed until they have the most advanced form of AMD before injecting an eye with drugs that actually fail to target the underlying disease process. Significant tissue damage and visual loss may have already taken place and, further, some patients respond poorly to these treatments.
A note about VEGF: VEGF, or Vascular endothelial growth factor for those in the know, is a small protein that promotes blood vessel growth. Given that excessive blood vessel growth is a major feature of wet AMD it is perhaps not surprising that therapies directed against VEGF were quickly employed. Anti-VEGF is an antibody that perturbs VEGF function, thus stopping blood vessel growth when applied directly to the site of disease. One problem, however, is the transient nature of this treatment and explains why patients are constantly needing injections to keep up the levels of anti-VEGF, or face the consequences of the blood vessels growing again. Herein lies the greatest criticism of anti-VEGF treatments, that it only slows down, or stops the final stages of the disease, and does nothing to address the underlying problem or prevent it in the first place.”
Furthermore, with a new delivery method come new opportunities for therapies and treatment may no longer be the preserve of the wet form of AMD.
However, we still have no treatments in routine use for geographic atrophy, which is thought to affect over 8 million people worldwide. We need to understand that dry AMD is a multi faceted disease, which can only be cured if treated in its very early stages and indeed linked to the underlying disease process and a patient’s specific genotype.
4.8 Micropulse laser for drusen removal
Professor Victor Chong
Head of Department – Oxford Eye Hospital
“Drusen” is the name given to small yellow deposits in the retina, which is often described as the first signs of AMD. They sit between the vascular supply of the retina (choroid) and the light sensitive photoreceptors for vision. Increase number and volume of drusen increases the risk of significant visual loss and common symptoms include difficulty with reading and adapting to changes in light.
The concept of using laser to remove drusen is not new as it has been used since the 1990’s. However, traditional laser causes scarring and can lead to conversion to wet AMD. Unfortunately, the current “rejuvenation laser” 2RT laser is also understood to cause scarring albeit much reduced compared to previous procedures. So another laser is in use by a growing number of consultant ophthalmologists, the “micropulse” laser, which is used extensively in diabetic patients and patients with serious central retinopathy for many years. The Micropulse laser delivers the laser energy in short pulses, and the treatment parameters have been tested in diabetic patients for over 10 years leading to the biological benefit without any scarring. The assumption is that drusen removal will have short term benefit in improving nutrient supply for the photoreceptors, but the long term benefits remain unclear.
4.9 Operating microscope with integrated OCT helping to refine surgical procedures in gene therapy
Director – Visionbridge
Following the successful world’s first Phase I gene therapy trial for choroideremia, Professor Robert MacLaren and his team at Oxford University and the Oxford Eye Hospital at the John Radcliffe Hospital have started a Phase II trial enrolling 30 patients.
In this trial Professor MacLaren is using an operating microscope with integrated optical coherence tomography (OCT) that will refine the surgery that is integral to the gene replacement therapy. The purchase of this vital piece of equipment called OPMI Lumera 700 Rescan is thanks to a number of funders including: National Eye Research Centre, The Tommy Salisbury Choroideremia Fund, Choroideremia Research Foundation USA, Hospital Saturday Fund, Fight for Sight and benefactors of the MacLaren Group. The project has been funded by the Efficacy and Mechanism Evaluation (EME) Programme, a Medical Research Council (MRC) and NIHR partnership.
Choroideremia is an incurable genetic condition affecting approximately 50,000 men worldwide. It is caused by a genetic fault in the REP-1 gene and gene therapy is being trialled to replace the faulty gene with a healthy one. The intraoperative OCT microscope enables surgeons to track changes in the retinal anatomy in real time and thereby permit safe and precise delivery of the gene therapy with the ultimate goal of improved vision for patients.
Professor Robert MacLaren, said: “On behalf of the Clinical Ophthalmology Research Group at the University of Oxford I would like to thank all its generous benefactors for assisting us in raising funds for an OCT operating microscope for the Oxford Eye Hospital. The equipment is being used in exciting new gene therapies for the treatment of patients suffering from incurable eye conditions. By using the OCT operating microscope it allows for better and safer outcomes for patients due to more refined surgery using the microscope.
If successful this trial can be translated to other conditions such as retinitis pigmentosa (RP) which affects 1 in 4,000 people in the UK.
4.10 Stem cell therapy for retinal degeneration
Dr. Anthony Vugler
Lecturer in Retinal Neurobiology
UCL Institute of Ophthalmology, London
Various sources of retinal stem cells are currently being investigated for their capacity to slow the progression of vision loss in degenerative retinal disease. Two major strategies are being pursued: 1. Cell replacement, 2. Preservation of retinal cells using neuroprotective factors.
For conditions such as Retinitis Pigmentosa (RP), where photoreceptors called rods degenerate followed by cones, cell replacement is being attempted using retinal progenitor cells derived from pluripotent human stem cells (human embryonic stem cells). These cells have shown the ability to integrate into the retina and restore function in animal models of advanced rod (photoreceptor responsible for peripheral vision and seeing in dim light)-/cone (photoreceptor responsible for seeing detail and colour) dystrophy.
The second and alternative approach seeks to slow the rate of rod / cone death by transplanting retinal cell types which produce neuroprotective substances, such as neurotrophic factors and anti-oxidants. As these cells do not need to respond to light and drive neural circuits within the retina, it is preferable that they are either encapsulated in the vitreous cavity of the eye, or, if they are to be delivered directly to the retina, that they integrate in a manner that does not interfere with signal transmission through existing circuitry. As such, glial support type cells (surrounding neurones and providing support and insulation), which lack neural activity, are well suited to the task. Indeed, these cells are capable of integrating into retinal circuitry in a way, which does not degrade normal vision. They can also preserve vision in animals with outer retinal degeneration and are currently being trialed in patients with RP.
In addition to outer retinal degeneration, stem cell derived neuroprotection is also being tested in animal models of glaucoma, with a view to preserving retinal ganglion cell survival / function in patients.
4.11 Gene therapy – prevention therapy supported by early diagnosis
Director – Visionbridge
Many inherited eye diseases are caused by a small variation or mutation in a single gene – the equivalent to a misspelling in an instruction manual. So, designed to rewrite this so called manual, gene therapy can deliver billions of healthy genes to replace a defective gene via an injection of a tiny drop of liquid underneath or near the retina. The new genes are carried to the target cells by specially designed viruses.
Innovative research around gene therapy to achieve improvements in visual health is ongoing in a range of top laboratories and hospitals across the UK. For example, studies into rare conditions such as choroideremia which causes progressive vision loss leading ultimately to complete blindness, have led researchers at Oxford University to conclude that the effects of gene therapy are potentially permanent and could therefore provide a single-treatment cure for many types of inherited blindness. These include retinitis pigmentosa which affects young people and age related macular degeneration (AMD).
There has been a lot of justifiable excitement about the potential of gene therapy, but there are calls from the research community not to overhype the results as it may be decades before these treatments become widely available.
Gene therapy also highlights the importance of early diagnosis followed by early preventative medical interventions, because as eye diseases progress in their severity, they become increasingly hard to treat with gene therapy. One leading researcher believes this is one reason why only half the patients in one early clinical trial benefited. So, the ultimate aim of gene therapy specialists will probably be to correct faulty genes before disease starts, before patients are aware that anything is wrong. To put this into context, currently there are tens of thousands of children in the UK who have eye conditions for which there is no effective treatment. Genetic eye screening may also provide a model for other branches of medicine, enabling millions of patients to bypass the trauma of inherited blindness.
4.12 Alternative treatment for glaucoma to circumvent shortfalls in drugs and surgery
Dr Colin Chu
NIHR clinical lecturer at the Bristol Eye Hospital and University of Bristol working with Professor Andrew Dick on
Glaucoma is the leading cause of irreversible visual loss worldwide and an estimated 12.5 million people world wide will be completely blind from the disease by 2020. Clinical trials have shown that reducing the pressure in the eye can prevent loss of vision from the commonest forms of glaucoma. Treatment using eye drops has been available for many years, but they are expensive, have side-effects, need lifelong use and often don’t reduce the pressure enough. Surgery is effective, but requires highly trained surgeons, is potentially high risk, has a relatively long recovery period and can fail over time.
So, more effective treatments are needed, particularly for use in the developing world where these same limitations are prohibitive and one such example is Dr Colin Chu and his team’s work at Bristol University in gene therapy using engineered viruses to re-programme cells of the eye. This has been shown to be safe in recent clinical trials and explores the use of the same viruses to infect cells of the ciliary body, the part of the eye responsible for continually producing aqueous humour – the fluid that maintains the pressure of the eye.
Using human ciliary bodies donated for research from the Bristol Eye Bank, Dr Colin Chu will programme the virus to deliver components of a system called CRISPR. This can cause genes to be accurately disrupted to stop them from making their encoded proteins. At this stage, genes known to be critical to aqueous humour production will be targeted. In theory this approach as a treatment could allow lifelong reduction in eye pressure following a single injection.
4.13 The potential of stem cell therapy in retinal disease
Director – Visionbridge
Stem cells have the potential to save the sight of hundreds of thousands of people with age-related macular degeneration (AMD), the UK’s most common form of vision impairment. AMD causes central vision loss, making it hard to drive or read. The macula lies in the centre of the retina where incoming rays of light are focused.
So, there is justifiable and growing excitement around the so called London Project launched in 2007 and the ongoing stem cell research and clinical trial led by Professor Pete Coffey at Moorfields Eye Hospital and the UCL Institute of Ophthalmology, who are running an experimental stem cell treatment on ten patients, supported by a stem cell specialist Professor Harry Moore, now co-director of Sheffield’s Centre for Stem Cell Biology. His team developed the stem cell line Shef-1 for the London trial. Shef-1 is derived from one-week-old embryos comprising about 100 cells. Such cells have the potential to develop into any type of cell in the body. Adding different growth factors induces cells to develop into different cell types. Developing Shef-1 took many years and involved extensive safety monitoring.
If successful, the technique could be available on the NHS within two-and-a-half years. The procedure, which has attracted the support of medical giant Pfizer, is carried out under local anaesthetic.
It involves taking a single embryonic stem cell and growing it into a 6mm patch of 100,000 retinal pigment cells.
That patch is then rolled into a thin tube, which is injected through a tiny slit in the eye.
Once unfurled, it is placed behind the retina where scientists hope it will replace the faulty cells. The first step has been carried out on the wet form of the condition when a patient bleeds at the back of the eye. But scientists are confident it could also be used for the more common dry AMD, which affects over 85 per cent of British sufferers.
Indeed, Pete Coffey has also confirmed that his team has developed an affordable and effective stem cell replacement for retinal damage from dry AMD. In the project’s first stage, researchers used human embryonic stem cells to regrow retinal pigment epithelium cells on an artificial membrane, creating a specialised patch. This patch was then surgically inserted, in a 45-minute Moorfields operation, into the middle of the retina in the trial patients. The research has now entered the second phase, where instead of receiving an artificial membrane with just retinal pigment epithelial cells on, patients have received a patch with all three layers of the retina, including blood cells, vascular cells, neural cells and support cells – essentially rebuilding the whole macula
The key point here is that these cells have been derived from the patients themselves. Pete Coffey will be using four genetic switches on a piece of skin thus creating the “beginning cell” that made each patient. The use of the patient’s cells has meant that their DNA could also be studied at the same time, potentially allowing for a personalised diagnosis of their condition as well as an individualised treatment.
Following the second stage, which is being funded through a £3m donation from the Michael Uren Foundation, regulatory approval for general patient use will be sought. As long as Pete Coffey and his team can show that there is good safety and good visual outcomes, then they can approach government and ask if they can go through a new advanced therapeutic route, which will allow that therapy to go quickly into the NHS. If these therapeutics are proven to work, they could save the NHS millions of pounds simply because the restoration of sight (to whatever degree) could provide independence and mobility to many thousands of patients again.
4.14 Repurposing a drug
Professor John KG Dart
Hon. Professor, University College, London
Scarring conjunctivitis is a major cause of chronic pain and sight loss. The conjunctiva is the membrane that lines the eyelid and covers the eye. In health, it helps lubricate and protect the eye, but in conditions such as ocular mucous membrane pemphigoid (ocular pemphigoid), severe eye allergy, Stevens-Johnson syndrome and trachoma, the associated inflammation triggers rapid pathological scarring, which often persists after the inflammation has gone, destroying the protective functions of the conjunctiva.
Currently, standard treatment for both mucous membrane pemphigoid and its ocular form is to suppress the immune system. This controls inflammation when it works, but there are unpleasant side effects and it has little effect on scarring. Approximately 1 in 5 people with the ocular form go blind.
Therefore, the aim of Professor John Dart’s research project at UCL Institute of Ophthalmology in collaboration with Moorfields Eye Hospital and Duke University School of Medicine was to identify potential therapeutic target molecules and provide a test bed for treatment. So the enzyme ALDH1 was identified as critical for one step in the process of turning vitamin A into retinoic acid – a key protein in immunity, inflammation and scarring.
The chosen therapeutic drug Disulfiram is a drug that’s licensed for treating alcohol abuse. It works by blocking ALDH activity, including ALDH2, which processes alcohol. Laboratory tests have demonstrated that inhibiting ALDH1 activity with disulfiram effectively reduces inflammation and prevents scarring in vivo, and significantly reduces the signs of scarring in vitro, in human ocular pemphigoid fibroblasts.
It may be that this approach will be more effective at scar prevention when there is active inflammation, but John Dart and his team have confirmed that this is an important proof-of-concept that currently untreatable scarring conjunctivitis may respond to eye drops or other topical application of a drug that can be repurposed.
4.15 Translational research for blinding surface diseases of the eye – including the cornea
Professor Julie Daniels
UCL Institute of Ophthalmology
Mr Sajjad Ahmad
Moorfields Eye Hospital and UCL Institute of Ophthalmology
Diseases of the surface of the eye (including the cornea) result in both painful and blinding eye disease. As per World Health Organisation statistics, corneal disease is one of the most common causes of blindness globally. The main focus of clinical need driven basic science research in this area include:
- Development of cell therapies for corneal tissue replacement:As a result of our ability to grow stem cells of different layers of the cornea in the laboratory, targeted replacement of abnormal corneal cells has become possible. One such therapy is limbal stem cell therapy for blinding corneal surface disease and this has traversed the translational and regulatory pathway to successful clinical trials and is under-going NICE evaluation. This process has paved the way for developing cell therapies for other layers of the cornea and indeed for other tissues of the eye. One such approach is the development of stem cell-populated biomimetic collagen tissue equivalents, known as “RAFT”, that is anticipated will enter clinical trials in the near future.
- Understanding the biological processes resulting in corneal diseases: In order to prevent the need for corneal replacement therapies, understanding the causes and contributors of corneal diseases are important. There are several examples of research within this field that have led to successful clinical applications. One such example is the use of cross-linking therapy to strengthen the cornea in keratoconus, a common corneal disease affecting young patients, and this has reduced the need for corneal transplantation and subsequent life-long monitoring.
- Biomarkers for corneal diseases and their severity: We are studying patients and their biological samples (blood and tissues) with rare blinding corneal diseases such as the genetic disease of aniridia related keratopathy and the drug toxicity induced Stevens-Johnson syndrome. We have large cohorts of patients with these diseases and we are seeking ways in which we can identify biological features (or biomarkers) that result in some patients having more severe corneal disease. By identifying these biomarkers early on in the disease process, we can provide closer monitoring and personalised treatments for such patients.
Although corneal diseases often result in eye pain and account for a significant proportion of blindness both nationally and globally, research in this field is poorly funded. The impact of clinically relevant corneal research is significant to patients, society and indeed to medical research as a whole. One such area of translational research is the development of a corneal cell therapy for chemical eye burns. This is the first stem cell therapy in any disease to be approved by the European Medicines Agency.
4.16 Nutrition that enhances vision in patients with retinal disease
Professor John Nolan
The macular carotenoids lutein (L), zeaxanthin (Z) and meso-zeaxanthin (MZ) selectively accumulate in the central retina (macula lutea), where they are collectively referred to as macular pigment (MP) (1; 2). The anatomic (central and prereceptorial location), biochemical (antioxidant and anti-inflammatory) and optical (short-wavelength [blue] light-filtering) properties of the macular carotenoids make these ideal candidates to enhance vision and protect against age-related macular degeneration (AMD). The light absorbance spectrum of MP peaks at 460nm and therefore this optical filter has the capacity to absorb/filter high energy short-wavelength (blue) light before it reaches the photoreceptors (the cells of vision) (3). This light-filtering process minimises ”chromatic aberration”) de-focused light) and light scatter, contributing to an improvement in visual function.
Indeed, this has been confirmed by Professor Nolan’s group via the ERC-funded (starter grant; 281096) CREST study (4). Also, MP’s constituent carotenoids are powerful antioxidants and are believed to reduce oxidative stress at the retina (5; 6). Our recent clinical trials in patients with early AMD have shown that optimising MP in patients with early AMD greatly improves visual function in these patients,(7) and other work from Moorfields London has demonstrated the importance of enriching MP in patients with other forms of retinal disease (e.g. diabetic retinopathy).(8)
It is important to point out that, although Professor Nolan and his team value the importance of optimising nutrition using standard dietary methods, the scientific studies conducted to date show that supplementation is required to achieve optimal tissue concentrations of the macular carotenoids. It is Professor Nolan’s view that humans are deficient in certain carotenoids and that this is in part due to intensive farming of foods for human consumption, resulting in carotenoid-deficient food. To this point, a typical European diet, contains only circa 1.5 mg/day of the macular carotenoids, whereas, it has been shown that at least 10mg/day of these carotenoids are required to achieve optimal tissue concentrations.
Antioxidants are man-made or natural substances that may prevent or delay some types of cell damage. Antioxidants are found in many foods, including fruits and vegetables. They are also available as dietary supplements. Examples of antioxidants include Beta-carotene, Lutein, Lycopene, Selenium, Vitamin E
Carotenoids: Any of a class of yellow to red pigments found especially in plants, algae, and photosynthetic bacteria. They have a wealth of health benefits, from giving us vitamin A to providing our bodies with antioxidants.
4.17 Pharmacogenetics: facts, estimate of potential and benefits of implementation in ophthalmology
Dr Pirro Hysi
Senior Lecturer in Ophthalmology
King’s College London
Most of the adult population in industrialized countries takes prescribed medication. Taking the USA as an example (it benefits from better statistics drawn from a larger market with socio-economic similarities with the UK and are currently the only statistics available), as much as 80% of adult Americans take at least one and almost 30% is prescribed five or more different medication at any given time.
Adverse Drug Reactions (ADR), defined as a harmful, unintended or more generally undesired response to medication, are common, of which 700,000 cases are annually reported in the US each year, resulting in 120,000 episodes of hospitalization and they are the 6th leading cause of death in the US.
There is also a large variation in medication efficacy, most of which is genetically driven. As much as 95% of the population carries at least one variant which would cause a clinically important variation in drug response , which could be prevented if the genotypes were known prior to medication intake (“actionable variants”). Pharmacogenomic drug labelling is available for approximately 160 currently marketed drugs, none of which is used in ophthalmology, although there are multiple ongoing clinical trials on the efficacy of ranibizumab for age-related macular degeneration (AMD). Pharmacogenomics, as an important component of personalized medicine is becoming more popular in recent years, with multiple initiatives generously funded by taxpayers under way in the United States and many smaller initiatives, mostly at the inception stage in the United Kingdom. Drug response variability is strongly genetic in 1/6 of the drugs.
Not all the drugs will show variability, in other words the same predictable response in all patients will be recorded. However, when this response is variable, heritability tends to be high. Put simply, if the drug response varies, this is largely genetic in most cases.
Identifying determinants of the efficacy of the drug in individual patients can save considerable time, reducing the strain of very busy practices and shortening waiting timesby cutting the number of visits that the current “trial and error” approaches entail. For example, the only treatment for glaucoma to date consists in medication that lowers internal eye pressure (IOP), of which two classes are particularly popular: is β-adrenergic agonists and in the last decade Prostaglandin Analogs (PGA). However, as many as 28% of treated patients do not respond to β-blockers (timolol) and 18% fail to respond to PGA (latanoprost) and an unknown number of patients somewhere between a full response (IOP reduction by at least 30%) and no response at all.
In the absence of adequate funding for eye research, most studies of response to IOP lowering treatments are carried out in small samples, with limited power. Yet, despite these limitations, studies show that perhaps as much as 80% of the variability of response to latanoprost may be determined by known DNA polymorphisms (unpublished studies, Hysi and Hammond, KCL Department of Ophthalmology). More work is needed to further evaluate the exact heritability of response to IOP-lowering medication and to identify the main DNA variants responsible for it.
In other areas of medicine, these approaches have been particularly fruitful. The hope is that pharmacogenetically guided treatment will become a reality for most classes of drugs as is currently the case for many cancer (for example olaparib) and cardiovascular (for example warfarin and clopidogrel) drugs.
4.18 Corneal wound healing research and Corneal drug delivery
Consultant Ophthalmic Surgeon
Clinical lead – Cornea and Cataract Service
Cambridge University Hospitals NHS trust
Visiting professor of ophthalmic and visual sciences
Vision and eye research unit (VERU)
Postgraduate medical institute
Anglia Ruskin University
The human cornea is a transparent structure that acts as a window to the eye. It is formed of collagen interspaced between cellular layers and basement membrane organised in five distinct layers. It is also an immune privileged site in the human eye due to its avascular (lack of blood vessels) nature. The loss of transparency and clarity to human cornea due to afflictions like infection, trauma and dystrophy is a leading cause of blindness (corneal blindness). Recent advances in wound healing research have improved the understanding of corneal cellular response to injury.
The cell kinetics vary significantly between the corneal epithelium (outermost layer of the cornea), stromal keratocytes and the endothelium (single layer of cells on inside of cornea facing the chamber between cornea and iris), with cytokine (A small protein released by cells with a specific effect on interactions between cells and on the behavior and communication between cells) mediated interactions and collagen (makes up to 30% of protein in the human body)reorganisation.
Innovations in surgical techniques aimed at corneal reshaping (laser refractive surgery) and corneal transplantation were based on the understanding of healing mechanisms. Millions have benefited from vision restoring procedures. Presently, there is a significant drive to develop an artificial cornea to address the growing demand for human donor corneas to tackle corneal blindness.
Cell based strategies (stem cell therapy) and synthetic materials are being explored widely towards this purpose. Detailed knowledge of corneal healing mechanisms combined with cell modulation techniques will be the key to identifying a solution . In addition, therapeutics such as Nerve Growth Factor and ROCK inhibitors have gained manufacturing approvals for human use to promote corneal healing based on biological research, and there is an evolving role for gene therapy to treat corneal disorders in the future.
Drug delivery to human cornea forms another exciting aspect of Professor Rajan’s research profile. Improved methods to administer drugs to the eye and human cornea has the potential to transform practice patterns in eye clinics and could potentially benefit thousands of patients with huge cost savings to the NHS.
Already several sustained drug delivery devices are available and Professor Rajan’s research into novel contact lens polymers have shown great promise too. There is a substantial research need in this area and investigations into nanoparticles, microspheres, stem cells and implants have so far shown encouraging results to improve drug delivery to the cornea and human eye. However, a lot more understanding is required to bring forth the results of laboratory studies to bed side treatments
4.19 Surgical innovation – providing effective alternative treatments for glaucoma
Mr Keith Barton
Consultant Ophthalmic Surgeon, Glaucoma Service
Moorfields Eye Hospital, London
Glaucoma is the commonest cause of irreversible visual loss in the world. While the prevalence is low at around 1 in 1000 at age 40 in white Europeans, it increases dramatically with age toapproximately 1 in 20 in their 80’s. Treatment is lifelong and usually involves the long-term use of medication (eyedrops) to lower the intraocular pressure (IOP). These can cause a multitude of local side effects, from redness of the eyes to irritation and even allergy. More than 50% of patients with glaucoma require 2 or more different drugs to control the condition. The greater the number of drugs used, the greater the risk of intolerance due to local side effects.
With this in mind, surgery has always offered the potential to achieve better intraocular pressure control than medical therapy as proven in past randomised trials. For example, the most commonly used IOP-lowering procedure called “trabeculectomy”, has been shown in randomised clinical trials to be more effective than medical therapy and yet only approximately 2.5% of glaucoma patients have surgery each year. A lack of predictability and the risk of morbidity associated with the surgery have limited the popularity of this procedure, with most patients preferring to persist with mediations.
This situation may be about to change. After 2 decades of unprecedented innovation in the medical treatment of glaucoma, there are no new classes of pharmaceutical agents on the horizon, patients are less tolerant of the side effects of medication and have greater expectations than before. Coinciding with this change in expectations, a new class of glaucoma surgical procedures has evolved, such as the “iStent”, a 1 mm long titanium snorkel that can be quickly inserted into the drainage channels of the eye to reduce outflow channel resistance. Also, so called “minimally-invasive” or “micro-invasive glaucoma surgery“ ( MIGS) is promising to open up the possibility of a surgical solution for glaucoma to a much wider population compared to the previous trabeculectomy procedure. However, while many of the newer devices are only modestly effective in comparison with traditional surgery, they are, as the name suggests, truly minimally invasive and can be offered at the same time as cataract surgery to a wide population of glaucoma patients undergoing cataract surgery with almost no extra risk in return for the possibility of reducing or even eliminating the burden of medication.
Other devices now commercially available include the “Cypass MicroStent” which drains aqueous humor from the anterior chamber into a space behind the retina known as the supra-choroidal space and the Xen Gel Implant, a 6mm long hollow collagen noodle with an internal diameter of only 45 microns that drains aqueous humor from the anterior chamber to subconjunctival space. Other devices in development include the Hydrus, a nitinol Schlemm’s canal scaffold and the MicroShunt which drains, like the Xen, to the subconjunctival space. In addition, outside the MIGS category of devices there have been a multitude of surgical innovations including micropulse diode laser cyclophotocoagulation, high frequency focused ultrasound cycloablation, ab interno canaloplasty and gonioscopy assisted trans-luminal trabeculotomy.
The current boom in the commercialisation of MIGS and associated surgical procedures has cast a spotlight on glaucoma surgical innovation that appears only to be growing. It is likely that the next evolutionary steps will be in two directions. Firstly, the development and commercialisation of long-acting drug-emitting implants which can be injected into the eye or placed into either the lacrimal ducts or conjunctival sacs to provide medication for durations of one month or longer. Secondly, the development of intraocular pressure sensors that can be placed inside the eye at the time of cataract surgery and provide long-term continuous telemetric eye pressure measurements that are more accurate and more informative than current IOP-measuring methods.
In summary, the benefits of improved treatments for patients are obvious but the benefits to NHS England of evolving surgical procedures and devices are also clear to see. For example, the reduction of patients’ long term dependence on drugs, the minimising of disruptive side-effects of drugs, the introduction of minimally invasive surgery and long term emiting therapeutic implants and the opportunity to provide cataract removal in conjunction with glaucoma surgery are all strong illustrations of how repeat visits for treatment can be reduced, overall costs of drug treatments might be minimised, patient flow and surgery time-efficiency can be vastly improved and patients’ quality of life may be enhanced over the longer term.
4.20 The path from scientific research to a marketed medicine
Dr. Heather Giles
Chief Scientific Officer
Scientific discovery forms the basis for virtually every new medicine. Many new medicines can result from the discovery of one new molecular target and a key function of scientific research is to understand the role of that target, in health and disease. This process takes several years. For example, the molecule “VEGF” was discovered in 1983, and in the following decade researchers gradually pieced together its role in physiological processes and identified diseases where blocking VEGF action could result in therapeutic utility, including for (Wet) macular degeneration. This is the point where the challenge of making a medicine begins.
(Note: Vascular endothelial growth factor or VEGF is a signal protein produced by cells that stimulates new blood vessel growth. Overexpression of VEGF can cause vascular disease in the retina and other parts of the body.)
The science of drug discovery starts with making molecules that block, or activate the target, and show efficacy in animal models of disease. The molecule must also be ‘druggable’ – meaning that it can reach the target organ, exert the desired effect, does not cause undesirable effects in cells or animal models, and has the potential to be made in large quantities. This identification of a ‘drug candidate’ suitable to test in humans can typically take 5-10 years. The failure rate is extremely high, and less than 1 in 100 projects reach the clinical drug development stage.
The goal of drug development is not only to demonstrate clinical efficacy but also to show that the benefit to the patient outweighs the risks. This requires three development functions to be conducted in parallel: manufacturing, non-clinical safety, and clinical studies. A common misconception is that the development process is ‘cookie-cutter” but nothing could be further from the truth, as unique scientific challenges occur throughout. For example, effective drug delivery continues to be particularly challenging for topical ophthalmic drugs.
During clinical development, patient safety is paramount, therefore every aspect of the process is heavily regulated, mostly by internationally accepted guidelines. Early studies are in healthy volunteers, and then in small groups of patients. The goal is to identify a safe dose, potential side-effects and, of course, an indication of efficacy (Phase 1 and 2). Phase 3 ‘pivotal’ studies must provide statistically significant evidence of efficacy and long-term (at least 1 year) safety data. Generally, several thousand patients must have been treated prior to marketing authorisation. For example, in 2016 the FDA approved lifitigrast for use in dry eye disease. As a result of the small number of patients with this disease, approval was granted following clinical studies in about 1400 patients. However, the regulatory path was not without challenge and prior to final approval, an additional clinical efficacy study was required involving more than 700 patients at 42 clinical study sites. Additionally, more rigorous manufacturing controls had to be implemented.
It takes 7-10 years for a drug candidate to reach the market, with a 1:10 success rate. Even after this, there are final hurdles to overcome before a drug can be prescribed for a patient in the NHS, such as a positive pharmaco-economic evaluation by NICE.
Robert J. Lefkowitz, NL, once said that the basic unit of time for science is the decade. A VEGF inhibitor to treat macular degeneration reached the market in 2006, more than 23 years after the discovery of VEGF. The impact of this drug on reducing sight loss demonstrates that a long-term funding of basic and translational ophthalmology research results in successful new treatments.
4.21 Glaucoma: Translating Science into Solutions
Professor Sir Peng Tee Khaw
PhD FRCP FRCS FRCOphth FRCPath FRSBiol FCOptom (Hon) DSc FARVO FMedSci
The 10:10:10 challenge and re-energising the optic nerve.
Glaucoma is the leading cause of irreversible blindness in the world, currently affecting over 60 million people worldwide, and estimated to rise to 76 million by 2020 and nearly 112 million by 2040 (Tham, 2014). It is one of the most common neuropathies in the world. In the UK, the risk for glaucoma is predicted to increase to almost 10% in people over 75 and approximately 10% of UK blindness registrations are attributed to glaucoma (NICE, 2009).
The management of the disease, however, is challenging. Unlike an available one-off treatment for cataracts, the treatment of glaucoma is less straightforward. Eye drops are often considered impractical, costly and burdensome with patients sometimes struggling to adhere to their treatment. In the 2012 James Lind ‘Sight Loss and Vision Priority Setting Partnership’ report, glaucoma was identified as one of the 12 categories of sight-loss conditions around which patients and clinicians had unanswered questions. The highest ranked priority questions in glaucoma were “What are the most effective treatments for glaucoma and how can treatment be improved?”
Surgery is usually considered for glaucoma when medicines do not sufficiently lower eye pressure, but it is specialised surgery and, like other forms of surgery, can be associated with risk of further complications. In many parts of the world, it is the most practical treatment. Scarring during healing, for example, is the most common cause of failure of surgical procedures that treat glaucoma. As Professor Sir Peng Tee Khaw, Director of the NIHR Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology comments: “Our ability to control wound healing and scarring is the most important event which determines whether or not surgery succeeds.”
The Moorfields Safer Surgery System which has evolved from our iterative research, first introduced more than a decade ago, has improved the outcomes and consistency of glaucoma surgery throughout the world. The system, designed to be easily implemented, has evolved over the years to reflect new clinical research, and it requires the minimum equipment. There remains, nonetheless, room for significant improvement. Says Sir Peng: “The system still requires a lot of training and it is not 100%reliable as it is so reliant on the surgeon’s skill. It is also time consuming. We need a procedure that can be carried out very quickly.”
Fast, reliable and effective
Sir Peng’s ambitious goal for the future is what he has termed the ‘10:10:10 challenge.’ The challenge is to achieve 10 mmHg (millimeters of mercury) for 10 years and performed within a 10-minute procedure.
More specifically, its objectives include:
- 10 minute rapid, reliable, relatively simple, safe single surgical procedure using a device/drug under topical/local anaesthesia with minimal hypotony (soft eye) or other significant complications
- 10 mm of Hg pressure in the eye, achieved with minimal diurnal (day/night) or postural (lying/standing pressure) variation in virtually all patients
- 10 years or more duration of effect
“We have evidence that getting the eye pressure down to 10 mmHg stops the disease in more than 95% of patients for five to 10 years,” explains Sir Peng. “If you can get it working for 10 years, then it will probably work well for life. Furthermore, if you can do the operation in 10 minutes, then you can do it in the developing world. It would potentially revolutionise the treatment of glaucoma globally.”
“It is the only real answer for glaucoma in the developing world. If we want to really make an impact, then we have to have a one-off treatment that works really well.”
While Sir Peng acknowledges that this is indeed very ambitious, he is also certain that it is achievable. “Two areas must, however, be addressed first,” he stresses. “Firstly, we need a micro device to control drainage very precisely during surgery, and secondly, we need to control how the eye heals following surgery or it just heals up the drainage hole created.”
“We are now working on new micro flow devices and anti-scarring agents in our attempt to achieve 10:10:10 and we’ll be moving forward to try to achieve this target within the next few years.”
In parallel with this research, Sir Peng and his colleague Professor Astrid Limb are looking at ways to improve or ‘re-energise’ optic nerve function.
They had discovered some special stem cells,,named the ‘Moorfields Institute of Ophthalmology cells’, and isolated them from donor human eye. In one study, they found that these stem cells restored some vision in rats that had had damage, similar to that from glaucoma, to their retinal ganglion cells and their long nerves (Singhai, 2012). These stem cells induced a partial functional recovery of the Retinal Ganglion Cells (RGCs) / axons of the eye, the layer of cells necessary to carry signals from the light sensing photoreceptors of the eye to the brain,
Although the authors point out that the present study did not address the re-growth of the optic nerve, the results suggest that it may be possible to improve the function of RGCs enough to achieve significant clinical improvement in humans. Further research is certainly required, but these findings show the exciting evidence of recovery of visual function by transplantation of RGCs.
“It is vital that we look at pressure too as there is no point in making advances in stem cell transplantation if raised pressure will just kill the nerve again,” explains Sir Peng.
“We have improved glaucoma treatment significantly over the years, but 10:10:10 is really the biggest step. I think we can get close to achieving 10:10:10 within a decade.”
4.22 A drug delivery platform that empowers patients and reduces costs and pressures in the NHS
Dr Felicity de Cogan
Research Fellow, University of Birmingham
Institute of Microbiology and Infection
As has already been highlighted in this report, intraocular injections of anti-VEGF therapies to treat wet AMD are well established in the clinic. While the anti-VEGF therapies are effective at arresting the symptoms of wet AMD in a large number of patients, the delivery mechanism (intravitreal injections) have a risk of significant side-effects, such as infection, retinal tears/detachment, and poor patient compliance. The procedure also requires a sterile environment and trained ophthalmic staff to carry out each injection, which puts a huge strain on ophthalmology services in the NHS and abroad. With an increasing ageing population the burden of treatment for wet AMD will only rise.
To target this problem the de Cogan group at the University of Birmingham has developed a cell penetrating peptide (CPP) as a platform technology for ocular drug delivery. The peptide is mixed with the current anti-VEGF therapeutics ranibizumab and bevacizumab and applied topically as an eye drop. Animal studies demonstrated that after 6 minutes the therapeutic load is detectable in the anterior chamber and after 30 minutes in the posterior segment. The therapeutic once delivered to the posterior segment of the eye clears over 24 hours, suggesting a daily eye drop regimen. The CPP does not hinder the efficacy of the anti-VEGF. Animal models of choroidal neovascularisation showed the same anatomic outcomes whether the anti-VEGF is delivered by CPP or by intravitreal injection. This demonstrates great promise for translation into the clinic, as it will allow the current clinic stockpile of anti-VEGF therapeutics to be used while reducing the side-effects associated with the intravitreal injection-based delivery method.
The simplicity of this technology allows it to act as a broader platform to deliver a range of ocular therapeutics, in addition to anti-VEGF therapies. Research with collaborators at the University of Birmingham and Queens University Belfast has demonstrated the ability of the CPP to deliver a range of different therapeutics from anti-VEGF antibodies and proteins to siRNA and short sequence peptides. The CPP can be simply mixed with the appropriate drug and applied topically as an eye drop. This means that the potential of this technology is not limited solely to AMD but can be used to treat other posterior segment diseases such as diabetic maculopathy and macula oedema. Ongoing work in the field of glaucoma has also shown its potential for delivery to the anterior chamber to allow the treatment of glaucoma.
The aim of this research is to drive drug delivery in ophthalmology forward to a point where injection-free ophthalmology treatments can be reached. This has the double goal of empowering patients and assisting them to take control of their own treatment while simultaneously reducing the financial burden for the NHS and other healthcare providers. It also raises the possibility of the care of these patients transferring from hospitals to primary care. While significant progress has been made on this and other technologies in the field of ophthalmology, translation to the clinic will not arrive without funding to bridge the gap between bench and bedside. Significant resources are needed to develop academic ideas through clinical translation to change these treatment regimens.
4.23 Protecting and regenerating the optic nerve in glaucoma with gene and stem cell therapies”
Professor Keith Martin
Professor of Ophthalmology, University of Cambridge
Honorary Consultant Ophthalmologist, Cambridge University Hospitals NHS Foundation Trust
Glaucoma affects over 60 million people worldwide. Blindness occurs through damage to the optic nerve, which transmits visual information from the eye to the brain. Reducing the eye pressure medically or surgically is currently the only treatment that can slow the progression of glaucoma, although visual deterioration continues despite treatment in many patients. There is an urgent need for new treatments that can prevent blindness in the most severely affected glaucoma patients, and restore some useful vision to those who have lost their sight due to the disease.
Keith Martin is a clinician scientist glaucoma specialist based at the John van Geest Centre for Brain Repair in Cambridge where he is working to develop new treatments for degenerative eye diseases, using stem cells, gene therapy and other approaches to regenerate the injured optic nerve. He works in an environment where he is constantly interacting with researchers working on other neurodegenerative conditions such as Parkinson’s disease and Alzheimer’s disease as well as other researchers working at the forefront of axonal degeneration research, spinal cord repair and remyelination. They share many interests and technologies as well as ideas in their joint quest to improve the lives of our patients. The ultimate aim of his work is to reduce the terrible burden of blindness caused by optic nerve diseases in the future.
A current focus of the Martin lab is modulating neurotrophic factor signalling pathways to improve neuronal survival. It has been shown that brain-derived neurotrophic factor (BDNF) delivery to the retina is reduced in animal models of glaucoma and that retinal delivery of BDNF by gene therapy can improve retinal ganglion cell (RGC) survival in experimental glaucoma, at least transiently. Work in the Martin lab has shown that human, mouse and rat cells can be targeted to produce BDNF and TrkB proteins simultaneously and that in animal models of optic nerve injury, treatment with both proteins is more protective than either given alone. Importantly, the use of gene therapy does not appear to have a negative impact on retinal health and the beneficial effects can be seen for long periods after a single treatment. A current major focus for the lab is to move a gene therapy strategy based on this work through to early stage clinical trials.
Another major focus for the Martin lab is developing strategies to enhance optic nerve regeneration after injury. Damage to the optic nerve is often accompanied by an inflammatory response and formation of a scar. Components of this scar include proteins called chondroitin sulphate proteoglycans (CSPGs). CSPGs may promote or inhibit nerve growth based on the pattern of sulphur atoms attached to chains on the protein. The lab is currently working to modify the levels of inhibitory CSPG at the injury site and enhance RGC axon regeneration. By reducing the inhibition caused by CSPGs and combining with other strategies to stimulate RGC to regenerate, they aim to enhance optic nerve regrowth after injury for the benefit of patients in the future.
4.24 Establishing the UK as the stem cell therapy hub for Retinal Diseases
Manager of Scientific and Medical Communications
ReNeuron Group Plc
ReNeuron is a leading clinical stage company focused on development of stem cell products for therapeutic use. ReNeuron’s approach is to develop allogeneic “off the shelf” cell therapy products using proprietary technologies for manufacturing on a commercial scale.
We have developed human Retinal Progenitor cells (hRPC) as a therapeutic candidate to treat blindness-causing diseases of the retina. The hRPC technology is aimed to provide protection to photoreceptors (rod and cone cells) when transplanted into the affected retina and may replace damagedcells. In pre-clinical studies, hRPC administration improved survival of retinal tissues along with visual acuity in rats with genetic defects that model inherited retinal diseases. There is also evidence that these hRPCs can develop into rod-like photoreceptors in culture and after transplantation into animals with retinal damage.
ReNeuron’s primary disease indication for use of the hRPC product is Retinitis Pigmentosa (RP). In RP, there is an initial degeneration of rod cells that are the photoreceptors in theouter retina and can also affect cones in the central retina.Visual deficits begin with the loss of peripheral vision that leads to night blindness and tunnel vision. This loss of vision progresses centrally and can eventually lead to blindness. RP is caused by genetic defects that may be either inherited or sporadic (occurring within the patient). Vision loss is first noticed in younger people and they tend to lose most / or all of their site by the time they are middle-aged. RP occurs in roughly 1 of 4,000 people. Although a number of therapeutic approaches to treat RP are in clinical trials, currently, there is no cure.
A Phase 1 / 2 clinical trial in RP patients has commenced in the United States in collaboration with the Massachusetts Eye and Ear Infirmary (Safety and Tolerability of hRPC in Retinitis Pigmentosa, NCT 02464436; ClinicalTrials.gov).The hRPCs are injected into the retina using standard surgical techniques and approved devices. Increasing doses of the cells (250,000 to 1 million) are being injected to investigate their safety. Patients are not treated with immunosuppressants as the cells do not initiate immune reactions and are not rejected by the body. Once safety of the cell administration has been determined, further efficacy studies will be performed using the maximum tolerated dose.
ReNeuron intends to expand its hRPC retinal cell disease programme into a further indication, Cone Rod Dystrophy(CRD). In contrast to RP, where the initial impact is a loss of rods, CRD is associated with a loss of cone cells in the retina. This disorder initially results in deterioration of central visual acuity and colour vision. CRD is an inherited disease that affects patients in childhood and is present in 1 of 40,000 people. As with RP, there is no cure for this condition.
ReNeuron has licenced the intellectual property associated with the hRPC product. Manufacturing processes have been developed for the expansion of the cells using low-oxygen culture environments. This approach allows the company to grow the cells on a scale suitable for commercial use. Further development has led to a frozen formulation of the cells,expanding their shelf life and facilitating logistics for global distribution. ReNeuron is establishing manufacture of the cells in the UK and will eventually base their production from its facility in Wales.
The hRPC programme has advanced with the help of long-standing collaborations with the Institute of Ophthalmology (University College London), Queens University Belfast and Schepens Eye Research Institute (an affiliate of Harvard Medical School). These academic institutions have expertise in the fields of inherited retinal diseases and degenerative retinal conditions aiding corporate sponsors in the translation of basic science to clinical trials. They provide specialist pre-clinical models of retinal degeneration to demonstrate proof of concept of stem cell administration. Once proof of concept has been established, biotechnology firms then transfer stem cell production to Good Manufacturing Practice facilities. This production within a Quality Assurance system is required to reach the high standards for cell administration in patients. Regulatory departments develop submissions to obtain permission from Competent Authorities to begin studies that are run by Clinical Trials teams. These latter activities require a broad set of skills and substantial funding that are provided by the corporate sector. The capabilities and cooperation of both sectors are essential to drive stem cell therapeutics forward as a credible option for retinal disease.
Research knowledge in RP is applicable to other retinal conditions associated with aging (Age-related Macular Degeneration) and diabetes (diabetic retinopathy). The administration of stem cells to protect “at risk” tissue and repair damage in the retina may also apply to these conditions. As the population of the United Kingdom ages, the prevalence of these degenerative retinal conditions will increase. This work in the development of stem cell therapeutics may well be important in treating increased numbers of patients with vision loss in the coming years.
Healthcare professionals cannot soley rely on the efficacy of a range of treatments to improve clinical outcomes for patients. Support is at hand to help them assess and even diagnose patients’ conditions as well as plan, explain and deliver appropriate treatments with the help of the orthoptic community backed by evidential research. There is also an impetus within the research community to challenge accepted rehabilitation practices and to focus on initiatives that can measurably deliver results. Technologies that enhance functional vision or deliver so called “artificial sight” in the form of intraocular and retinal implants as well as various tele-health devices to support treatment regimes and positive lifestyle choices and low vision aids to support everyday tasks, are very illustrative of the innovation driving the eye research community.
5.1 Orthoptic research spanning assessment, diagnosis and treatment leading to improved patient care
Professor Helen Davis –
Professor of Orthoptics
Academic Unit of Ophthalmology & Orthoptics
Department of Oncology & Metabolism
The Medical School
The University of Sheffield
Dr Anna Horwood
Infant Vision Laboratory
University of Reading
Dr Fiona Rowe
VISION research unit
University of Liverpool
At least 10% of the population will seek professional advice for squint, double or blurred vision, or eye strain at some time in their lives. For vision to develop normally, very tiny babies have to learn to co-ordinate accommodation (eye focusing to make near images clear) and convergence (pointing the eyes accurately towards objects as they move in depth) in the very first weeks of life: at the same time, or before, many other aspects of vision are also developing. Many common visual problems which crop up later in life happen because these systems do not develop normally in early childhood.
Dr Anna Horwood leads the Infant Vision Laboratory at the University of Reading. The lab’s research has ranged widely across many aspects of normal and abnormal visual development from birth to maturity in full-term and premature infants, as well as studying children with many common types of strabismus.
This research has produced results which have challenged long-held assumptions, providing a better understanding of how these systems work and how, and why, problems develop. This research helps eye care professionals target, plan and explain treatment options for their patients. By providing alternative and better explanations of how visual co-ordination works, improvements and efficiencies are being adopted in patient care.
Stroke is the most common cause of UK adult disability with about 100,000 new cases of stroke per annum. Post stroke visual impairment is just one disability that affects stroke survivors. Research from the VISION research unit at the University of Liverpool led by Dr Fiona Rowe aims to improve the orthoptic and vision care of stroke survivors with visual impairment occurring following their stroke. Their research has provided evidence on the prevalence and incidence of post-stroke visual impairment, the types of visual conditions experienced by stroke survivors, how best to screen and assess these visual conditions and what rehabilitation options can be considered for these visual conditions.
Post stroke visual impairment is broadly divided into four categories of impaired central vision, eye movement abnormalities, visual field loss and visual perceptual abnormalities. These may occur in isolation but more frequently occur in combination. Screening for visual impairment is essential and this research has led to the National UK recommendations for the integration of specialist orthoptist screening on acute stroke units. The UK population is aging and so improving care provision for stroke survivors is important and will continue to be a future need.
Investigation of binocular function and the ability to appreciate 3D vision is a pivotal investigation of patients with strabismus. Whilst there was evidence that the quality of distance 3D vision could influence the timing of surgery in some forms of strabismus there was a lack of ability to clinically test this particularly in the UK. Professor Helen Davis in collaboration with Professor John Frisby designed a test which has been validated for clinical practice and now used worldwide. There is a need to continue all aspects of Orthoptic research to provide better and more accurate assessment with a view to better targeted treatment regimes.
5.2 Technology combined with rehabilitation can improve quality of life for patients
Mr Felipe Dhawahir-Scala
Consultant Ophthalmologist and Vitreoretinal Surgeon
Director of the Acute Ophthalmic Services
Manchester Royal Eye Hospital.
The CentraSight™ Treatment Programme aims to restore some useful central vision in patients with bilateral end stage age-related macular degeneration who have significant bilateral visual impairment (visual acuity between 6/24 and 6/240 in each eye) by implanting the Implantable Miniature Telescope™ (IMT) in one eye.
This miniature telescope provides 2.7x magnification and a field of view of 20°. It works on the principal of a Galilean telescope and contains no electronics. It is implanted into the better-seeing eye after removal of the lens, taking up the position of the lens. The implant enlarges the image and projects it onto healthier areas of the retina outside of the macula (see figure below). Patients must undergo around 6 rehabilitation sessions post operatively to learn to adapt to the new visual status this creates: using the implanted eye for detailed tasks such as watching TV, recognising faces or reading and the non-implanted eye for navigation and depth perception. Participation in the rehabilitation process is vital to achieve full benefit from the programme. In suitable patients, the CentraSight programme has been shown to improve visual acuity and quality of life (Hudson, Lane et al. 2006, Hudson, Stulting et al. 2008).
Diagrammatic representation of effect of IMT
Patients are screened to assess their suitability for the programme. An external telescope simulator is used to simulate the magnification and field of view produced by the implant and the experience of having a magnified view in 1 eye and a non-magnified view in the other. This establishes whether a patient will experience an improvement in visual acuity with implantation and demonstrates the tradeoff between a 30° reduction in the field of view on the side of implant (i.e. if implant in the right eye, the reduction is on the right side) whilst improving the visual acuity in the implant eye. Not only must patients appreciate a subjective improvement with the simulator, they must also accept this tradeoff; therefore the CentraSight Programme may not be a solution for all patients with AMD.
The safety and effectiveness of the CentraSight Programme has been studied in a prospective, multicentre clinical trial (Hudson, Lane et al. 2006, Hudson, Stulting et al. 2008). 206 patients who have not had previous cataract surgery were implanted and followed up for 2 years. Data from a 5 year extension study has now also been published (Boyer, Freud et al. 2015).
A mean gain of 3 lines of ETDRS visual acuity was present both 1 and 2 years after implantation. At 5 years mean improvement was 2.5 lines.
Improved visual acuity was associated with a clinically significant improvement in quality of life assessed by the National Eye Institute Visual Function Questionnaire. These benefits are expected to translate into significant improvements in mental health; (Hudson, Lane et al. 2006); significantly fewer falls than would be expected in a similar aged population (Hudson, Stulting et al. 2008) and patients being better able to care for themselves and others, and to perform activities of daily living (Stevenson, Hart et al. 2004, Hudson, Stulting et al. 2008).
This year Mr Felipe Dhawahir- Scala implanted the first NHS funded patient at Manchester Royal Eye Hospital. It is hoped that the CentraSight Programme will be more widely available on the NHS in the future.
A further study is planned to examine the safety and effectiveness of the CentraSight programme in patients who previously had cataract surgery. This will take place over 3 sites in the USA, recruiting 50 patients initially, with an extension to 75 if results are favourable. It’s hoped this will open up this technology to patients with end stage dry AMD and previous cataract surgery.
5.3 An example of rehabilitation technology from abroad
Director – Visionbridge
A wearable assistive device has been developed for the visually impaired, which enables them to sense their environment and move around more safely. The device, which is worn like a heart rate monitor, has been clinically tested.
VTT Technical Research Centre of Finland has developed a wearable assistive device for the visually impaired, which enables them to sense their environment and move around more safely. The device, which is worn like a heart rate monitor, has been clinically tested.
“The device functions on the basis of a radar system developed by VTT. The novel aspect lies in wearable sensor device which functions based on radio waves so that the signal passes through clothing. This means that it can be worn discreetly under a coat, for example,” says Tero Kiuru, a Senior Scientist at VTT.
The radar conveys information to the user in the form of vibrations or voice feedback. It senses most obstacles in the user’s surroundings, although difficulties remain in sensing objects such as thin branches and bushes.
The radar has already been clinically tested in device trials approved by the National Supervisory Authority for Welfare and Health (Valvira), in which VTT’s partners were Kuopio University Hospital and the Finnish Federation of the Visually Impaired (FFVI). The test group included a total of 25 visually impaired people, of whom 14 were blind, 7 partially sighted and 4 were deaf-blind.
Feedback shows that a clear majority of the testers felt that the radar improved their ability to perceive their environment and increased their self-confidence when moving around. Indeed, a total of 92% of the trial users felt that the device helped them to perceive their surroundings, 80% felt that their trust in their ability to move around independently had increased and 32% would immediately start using the test device in its current form.
On the other hand, they were not satisfied with distance control and vibration-based feedback, so of course the research will continue with selected test users and the device will be further developed with a view to penetrating the global market of which there are up to approx. 300 million people with visual impairment or blindness.
5.4 The importance of reading tests and rehabilitation techniques
Professor Gary Rubin
Helen Keller Professor of Visual Function and Rehabilitation
Inst Ophthalmology – Visual Neuroscience
Institute of Ophthalmology
Faculty of Brain Sciences
In 1854, Edward von Jaeger introduced the first printed chart for measuring vision. This chart did not use individual letters and it did not measure visual acuity. That was left to Herman Snellen 8 years later. Jaeger’s chart used words and measured reading performance for brief sentences. The original Jaeger chart was very sophisticated. It tested in multiple languages and the original texts followed a geometric size progression, just as modern logMAR charts do today. The Jaeger charts are much-maligned for lacking standardization of sizes for charts made by different manufacturers and for following an irregular pattern of increasing sizes (J1, J2, etc). However, those faults lie with modern printers who failed to follow the original specification. In 1980, Ian Bailey and Jan Lovie-Kitchin introduced a new reading test called the Bailey – Lovie near reading card which contained unrelated words in a geometric progression of letter sizes, heralding the birth of the modern reading test.
There are now dozens of different reading tests in a wide variety of languages, all designed for measuring reading performance of people with impaired vision (low vision). Some use unrelated words or mixture of words and letters, others use meaningful text, from brief sentences to paragraphs. One test uses a long story that takes 30 minutes to read and measures reading endurance. The benefits of different types of reading tests how they are presented, scored, and evaluated is a complicated issue. But most agree that there are at least two important parameters that describe reading with low vision, maximum reading rate (reading speed under optimal viewing conditions) and critical character size (smallest letter size that allows the reader to achieve their maximum rating rate. Reading tests are widely used in clinical vision research. Reading performance has been studied in almost every eye condition ranging from amblyopia to cataract, glaucoma, and especially age related macular degeneration (AMD). Reading tests have been used as primary outcome measures for studies of the effectiveness of low-vision aids and rehabilitation, and as secondary outcomes in clinical trials dating back to the macular photo coagulation study (MPS) in the 1980s.
A strong interest in low-vision reading remains because obviously reading is important for maintaining independence and quality-of-life. This is reflected in data that was collected by Professor Gary Rubin and his team from an unpublished survey of 1000 consecutive low-vision patients seen at the John Hopkins Wilmer low vision clinic. Each new patient was asked what was the main reason for coming to the low vision clinic and more than 60% listed reading difficulty as their chief complaint followed by driving which was identified as a chief complaint for just over 5% of those surveyed.
That survey was conducted over 20 years ago and the research team wondered if reading still remains a priority bearing in mind the rise of digital communication. So, in-depth structured interviews were conducted with the small group of AMD patients recruited from the Moorfield’s low vision clinic. Researchers were surprised to find that reading difficulty remained a top priority for the interviewed patients.
So, what can be offered to today’s low vision patient who wants to improve their reading ability?
Of course, simple hand and stand magnifiers are the mainstay of low-vision reading rehabilitation. The optics have improved as has the illumination thanks to LEDs, but magnifiers have not changed much in recent decades. However, the widespread availability of electronic low vision aids has certainly changed the landscape, including apps that turn smart phones into a low vision reading device, dedicated portable electronic vision enhancement system, head-mounted video magnifiers and computer software that can convert printed text to speech and vice versa.
There is also a surgical solution for low vision patients with cataracts. In the normal procedure the cloudy crystalline lens is replaced with a clear plastic lens that has minimal impact on the optics of the eye. However, in this case the crystalline lens is replaced by a miniature telescope implanted directly in the eye that works with the cornea to provide up to 3X magnification. Of course, there is the hope that retinal implants (the chip in the eye) will one day have sufficient resolution to restore some reading ability to patients who would otherwise be blind, but to date that has remained a dream for future prosthetic retinal implants.
Recent research has identified several of the characteristics that limit reading performance in low vision patients. These characteristics include poor control of eye movements that guide the eye from word to word during the normal reading processes, or hold the eye steady to enable accurate decoding of the text. Another important factor is “crowding” which makes it difficult to recognize a word when it is surrounded by other words. Crowding is especially important in patients with central vision loss (such as AMD) who must rely on peripheral vision for tasks such as reading. Crowding is known to affect peripheral vision more than central vision.
All of these factors may improve with training. For example, Gary Rubin and his team know that patients with newly diagnosed AMD can learn to use their peripheral vision in place of the non-functioning fovea, learn to make more efficient eye movements when reading static text and that older readers can expand their visual span with perceptual training. To date, clinical trials of these and other rehabilitation strategies have had mixed results – for example, randomized controlled trials of eccentric viewing training do not seem to have an impact on the development of a peripheral location to take the place of the fovea, while eye-movement training seems to work. However, most importantly, there is a new interest in randomized controlled trials that provide the high-caliber evidence needed to secure funding for rehabilitation programs that work.
5.5 Enhancing the lifestyles of people who are blind and visually impaired
Marketing Manager UK
OrCam’s mission is to harness the power of artificial vision by incorporating pioneering technology into a wearable platform which improves the lives of individuals who are blind, visually impaired, have a reading disability or people with other conditions.
The breakthrough OrCam MyEye device provides is a visual aid through a discreet, wearable platform and easy-to-use interface.
An artificial vision innovator powered by leading minds in the Computer Vision and Machine Learning fields, OrCam’s team includes dedicated software, computer and electrical engineers, hardware design experts, and a passionate customer service team – including sighted, low vision and blind members. Indeed the team has spent years developing the innovative and responsive OrCam MyEye assistive technology device to read any printed or digital text, such as newspapers, documents, and signs, as well as recognise faces and identify shopping products. OrCam’s technology also incorporates helpful gestures such as telling the time and stopping the real-time text reading.
To address an ever-growing number of visually impaired people throughout the world, OrCam is making it their mission to assist in the emotional well-being and independence of those who suffer with visual impairment. OrCam’s revolutionary artificial vision technology is being further developed and their R&D team is working on future models that will make ‘difficult living’ for the blind a thing of the past.
Lateral potential for the OrCam has become more apparent as those who suffer with reading difficulties such as dyslexia are now benefiting from the technology. Challenges with reading text makes learning a lot harder than it should be, but not in the case of a young girl in Jerusalem who featured in the Washington Post who experienced OrCam MyEye. The Washington post noted, “As well as helping those with vision disabilities, MyEye could also assist millions of children to keep pace with their classmates even as they take a bit longer to learn to read or even if they never learn to read”.
This portable device not only offers convenience, but it also gives those who suffer from visual impairment the best opportunity to live a life away from home. Being completely reliant on another adds frustration, but OrCam helps positively alter the definition of a visually impaired lifestyle. However, like any other piece of technology, OrCam does have its limitations and does not enhance sight, but it does provide a level of independence which was previously absent.
A study of usability with the OrCam was conducted with a group of 12 individuals who had various low vision difficulties. Standard daily tasks were presented to all candidates with results indicating a struggle to perform. Following this, candidates were to perform the same tasks but this time they had the OrCam at hand. All 12 candidates could identify products and read text without the use of their low-vision aids
In conclusion, OrCam does not enhance a user’s vision level but it does greatly assist with advanced text-to-speech reading, product and face recognition, and overall provides enhancement of the daily living for those who experience sight loss and blindness. It is believed that OrCam is a unique device currently on the market. The combination of its advanced artificial vision technology and usability paired with its portable capabilities puts it in arguably a premium place for aiding the visually impaired.
5.6 Prototype Smart homes for the visually impaired”
Professor Barbara Pierscionek
Associate Dean of Research
School of Science and Technology
Nottingham Trent University
Visual impairment affects around two million people in the UK and is higher in older age groups with estimations of over 20% of the 75 year olds having difficulties with sight. Ageing is a prime risk factor for sight loss and the population age is increasing across the UK. As the number of older people in the population increases there will be a concomitant rise in visual problems. This will lead to a greater demand for solutions that will enable individuals with visual impairments to continue to live independently and engage fully and actively in employment. There is a need for early detection and development of adaptive technologies to support needs that arise with age and that are related to different forms of sight loss. The leading causes of visual impairment are those that are either primarily ocular: age-related macular degeneration (AMD), cataract, glaucoma or those that are secondary to systemic or neural conditions: diabetic retinopathy and neuro-ophthalmic disorders. In all of these conditions some residual visual function remains. Given the right environment this should be optimised to improve the lives of the visually impaired leading to better employment prospects, quality of life and economic benefit.
Legally there are measures in place to ensure that those with visual impairment are assured of accessibility to and usability of public spaces and services. Visual contrast is a requirement of Building Regulations Part M, 2010, and the Equality Act 2010 renders environments, products and services that exclude the visually impaired, an act of discrimination. This notwithstanding, there remain a myriad of untapped opportunities to improve the environment for the visually impaired such that the impairment is reduced and the visual function optimised. In addition, the diversity of visual impairments and the different functional losses that these produce need to be recognised so that appropriate methods and technologies can be applied to each condition to maximise visual function. A generic approach to visual impairment will not be effective for any condition.
The advent of Smart Homes and Ambient Assisted Living Technologies are facilitating a number of aspects of daily living for a wide range of people and are being advanced for the elderly and those with disabilities yet comparatively little has been done for the visually impaired. Developing prototype living environments that will maximise vision for a range of eye conditions will provide an enhanced level of independence and improved quality of life for individuals with visual impairments. It is also essential to understand the importance of correct lighting in creating environments that optimise contrast and object visibility whilst minimising glare.
The rationale underpinning this approach recognises that:
A.) Impairment is the combination of functional loss and environmental conditions and that the latter can be dynamically adapted to ensure that function is optimised;
B.) Visual impairments vary depending on which part of the ocular system is affected and all sensory functional losses need to be considered when designing intelligent environments such that each requires specific and appropriate technologies to be effective.
The research question is how best to develop and design prototype living environments that will provide the visually impaired with settings that maximise their visual capacity and provide an enhanced quality of life.
Despite the extraordinary scientific breakthroughs that may deliver invaluable improvements to the quality of patients’ lives, we must not forget the critical role that patients themselves can play in the development of a holistic, innovative and patient centred eyecare system. This point is not only reflected in the following contributory texts but also in the outcomes delivered by the James Lind Alliance (JLA) and the Sight Loss and Vision Priority Setting Partnership which has brought patients, relatives, carers and eye health professionals together to prioritise research activities. Eye research must also continue to support patients in helping themselves, remaining abreast of symptoms and the practical impact of sight loss as well as changing their behaviours so as to mitigate the risks of avoidable sight loss. Improved counselling and stronger interaction with healthcare professionals around the point of diagnosis for unavoidable and avoidable sight loss, better experiences for children in eye clinics and the greater knowledge gained by ophthalmic nurses in the management of glaucoma patients are more examples of how eye research can support practical solutions alongside scientific advances.
6.1 Patient Power – it actually works!
Professor Philip I. Murray
Professor of Ophthalmology
part of the Birmingham Behçet Centre of Excellence.
Behçet’s Syndrome (also known as Behçet’s Disease – BD) is a rare, chronic, multisystem disorder of unknown cause. It is typically characterised by recurrent mouth ulcers, genital ulcers, eye inflammation (uveitis), joint pain and skin lesions. The cause of BD is unknown, although most experts believe it is an auto-inflammatory condition, that is where the immune system – the body’s natural defence against infection and illness – mistakenly attacks healthy tissue. In cases of BD, it is thought the immune system mistakenly attacks the blood vessels. It is not clear what triggers this problem but BD tends to be much more common in certain ethnic groups where the gene HLA-B51 is linked to the condition, such as Turkey, the Middle East and the Far East. In the UK, it is estimated that there are about 1 in 100,000 – that is, about 1000 people with BD.
A relative lack in understanding of this disease, paucity of evidence and low prevalence in the UK has created some real challenges for accurate diagnosis, prognosis and disease management. Other problems around the delivery of care including inconsistent access to biologic treatment (Treatment to stimulate or restore the ability of the immune (defense) system to fight infection and disease – it uses the body’s natural abilities that constitute the immune system to fight infection and disease or to protect the body from some of the side effects of treatment) and the long interval from first symptom to diagnosis (typically more than a decade) and a pathway to diagnosis involving consecutive attendances with multiple specialists, often at different hospitals as part of the diagnostic journey, acted as a catalyst for change and a desire amongst patients (patient support group, Behçet’s Syndrome Society – http://www.behcets.org.uk) and experts interested in this disease to plan an optimal model for care provision.
Joint discussions have resulted in an innovative, holistic and patient-centred approach to care delivery including the routine collection of outcome data, supported by a system-wide approach to patient and practitioner education which has led to greater awareness and understanding of diagnosis and treatment options. The service is also accountable to commissioners through annual meetings.
Since 2012, three national centres (Birmingham, Liverpool, London) have been running a one-stop solution approach to delivering clinics each week in which experts from Rheumatology, Ophthalmology, Oral Medicine, Neurology, Dermatology, Gynaecology (or Genitourinary Medicine) are all working together to focus on patients. Each centre also has a manager (typically a highly-trained specialist nurse) who can pre-screen referrals, case-manage patients and co- ordinate care as needed to a custom process, matching individual care needs with the specialists available. While the service is commissioned for England, patients are also referred from other parts of the UK, Europe and internationally, with alternative methods of funding.
The service also provides clinical psychology support, to address bio-psychosocial factors and fatigue and pain management. A support worker is also made available to access support networks for non-medical problems and to signpost patients to appropriate help, that has previously not been possible.
The website of the centres (http://www.behcets.nhs.uk/) delineates the services and resources available for patients and healthcare professionals, along with a national drugs pathway (based on best available evidence) for guiding therapy. The support of the National Health Service commissioners was vital in providing a run-through budget that was allocated to centres and crucially enabled funding to promptly flow to local units (following a clinician- to-clinician discussion) for support of delivery of biologic therapy.
In conclusion, this intense, coherent and multi-disciplinary approach to rare or complex multisystem diseases is still evolving but represents an ideal platform on which to build. It was developed through strong collaboration between patient group and healthcare professionals to deliver a high-quality service, but also provides an important role in education and research. It seems to be cost-efficient for both patients and clinicians by facilitating rapid decision-making supported by funding for high-cost drugs at the specialist centres where the expertise is based. Enabling funding to flow locally, is a model with much relevance for other conditions and hospital design in general.
6.2 Understanding the complex health needs of the ageing population
Dr Denize Atan
SOCS Lead for Women in Science
Consultant Senior Lecturer in Ophthalmology
School of Clinical Sciences
F38, Biomedical Sciences Building
University of Bristol
Many common eye problems begin in the ageing population. The most common causes of blindness in adults of the UK in fact, are age-related macular degeneration (AMD) and glaucoma, which may both be considered to be age-related degenerative diseases. In addition, cataracts are an inevitable consequence of ageing. Compounded with the increasing prevalence of cognitive problems and physical disabilities in the ageing, the holistic management of elderly patients needs to take these factors into account. A new collaboration between Dr Denize Atan and academics interested in dementia, urinary tract problems, neuropsychiatry and renal medicine called ARCADIA (Alliance for Research into Complex and Chronic Disorders of Ageing) is investigating how these factors interact in solving the problem of incontinence. For example, bladder problems and nocturia (waking at night to urinate) are common in the ageing population and cognitive problems, visual disturbance and physical mobility problems compound each other leading to incontinence. The management of this problem will depend on addressing all of these issues.
The ARCADIA group has recently been successful in obtaining funding from the David Telling Trust to investigate the impact of kidney dialysis (a process of diffusing blood across a semipermeable membrane to remove substances that a normal kidney would eliminate, including waste products, poisons and drugs) on cognitive and visual function. Two camps of thought exist about the benefits and risks of dialysis – that the cognitive side effects of uraemia (the metabolic disturbances caused by renal failure) will be alleviated by dialysis so that cognitive function should improve during treatment vs the hypothesis that the large fluid shifts that occur during dialysis will actually lead to impaired cognitive performance. The retinal changes in patients with diabetes often get worse during dialysis which supports the latter hypothesis. This project will investigate the impact of dialysis on visual and cognitive function and will use advances in retinal imaging to look at fluid shifts in the retinal vasculature – an extension of the cerebral circulation. The outcomes of this research may well influence current guidelines on the recommended amount and frequency of haemodialysis.
6.3 Combining treatment and counselling to improve patient outcomes
Director – Visionbridge
New research from Manchester Royal Eye Hospital has concluded that despite the extraordinary scientific achievements in diagnosing and treating serious eye diseases such as wet age related macular degeneration (wAMD), which have revolutionised our ability to reverse life-changing vision loss, high levels of anxiety and depression persist in patients. Therefore all health care professionals must ensure that patients can reap the full benefits of this cutting-edge science.
Manchester based researchers say that the study findings demonstrate the value of human interaction between clinician and patient in offering reassurance around the efficacy and safety associated with anti-VEGF injections and highlights how factors such as patients’ understanding and building strong relationships with healthcare professionals may help alleviate anxiety around receiving injections. Patients may benefit from additional assurances from clinical staff regarding success rates in halting disease progression with anti-VEGF therapy, how it can reduce the risk of becoming blind in the future and the low likelihood of serious problems occurring following the injections.
These research findings also point to the importance of considering specialised counselling for certain wAMD patients – indeed, literature has shown that tailored psychological and psychosocial interventions can be effective to reduce anxiety and depression in wAMD patients and contribute to their adjustment to illness and medical treatments. Although levels of depression reduce once anti-VEGF therapy is established, doctors should be vigilant to such symptoms and their potential to impair quality-of-life. It is believed that the use of standardised tools to screen wAMD patients for symptoms of anxiety and depression in the macular treatment unit could better help identify patients at risk. Further research and controlled trials will be needed to better understand anxiety and depression in wAMD patients and develop new intervention tools at patient and clinical level to reduce symptoms and improve quality-of-life.
This study was supported by the National Institute for Health Research (NIHR). It was also funded by a grant from Bayer, in order to support the ophthalmology community in transforming care and supporting people living with retinal conditions.
6.4 Fighting infection and changing behavior
Professor John KG Dart
Hon. Professor, University College, London
Acanthamoeba keratitis (AK) is a rare corneal infectious disease caused by the pathogenic free-living protozoan Acanthamoeba spp. Incidence of the infection is low (1 in 100,000 in the EU), but has life changing consequences, due to the prolonged and painful infection, with half the patients requiring more than 6 months treatment, and severe loss of vision or blindness in 25%. In countries where contact lenses are commonly worn, lens use accounts for over 85% of cases. AK also occurs after corneal trauma, particularly in rural environments. AK is on the rise in developing economies and there is no approved drug to treat this disease.
There was little really effective treatment and what treatment there was did not help all patients. As a result, patients needed therapeutic corneal transplant surgery with poor outcomes and high morbidity.
So, Professor John Dart and his team at Moorfields eye hospital have applied epidemiological, laboratory and clinical research to identify avoidable risk factors, develop better techniques for diagnosis, and introduce and develop a class of disinfectants (the biguanides) as topical drugs for treatment.
This work has improved the prevention, diagnosis and treatment of AK. Indeed, guidelines for the prevention of AK now feature in correspondence and on websites of organisations associated with disease control and recommended use of contact lenses, highlighting risk factors such as swimming, extended-wear contact lenses, and hygiene related to contact lens cases.
The level of awareness of AK amongst Public and practitioners has been substantially raised due to a range of media articles, health campaigns and initiatives adopted by Moorfields Eye Hospital and the changes in packaging.
Also, newly improved contact lens cases and cleaning solutions have appeared on the market as a direct result of John Dart’s research that pointed to the ineffectiveness of certain chlorine based solutions in preventing AK.
6.5 The importance of integrating diabetic eye care with diabetes management
Dr Elizabeth Wilkinson
Clinical Lead, North and East Devon Diabetic Screening Programme
Dr Elizabeth Wilkinson, ex president of the Ophthalmology Section at the Royal Society of Medicine knows that managing diabetes is a complex issue. She is the Clinical Lead for the North and East Devon Diabetic Screening Programme and argues for better integration of diabetic eye care with wider diabetes management.
Despite the tremendous success of the National Diabetic Eye Screening service launched in 2003 (over 2 million people were invited for photographic diabetic eye screening locally during 2016 – All Type 1 and Type 2 diabetics over the age of 12 are eligible) and the emergence of pharmaceutical options in addition to laser treatment, pressures are increasing on the patient, their supporting family, hospital eye services and NHS budgets. All drugs now available are very expensive and cost the NHS at least £1,000 to deliver each time. Patients may need monthly injections and follow ups. The dawn of injectable drugs for retinal disease has had a huge impact on hospital eye services and it’s expensive in both time and money.
So, one of the solutions to this situation might be to recognize that the problem with diabetes is that it is a blood vessel disease, a whole body disease and symptom-free until late and not just an eye disease. Therefore it could be argued that the current pathways for patients with diabetes are focusing too much on the eye disease itself and in addition are not sufficiently integrated. Improvements in Diabetic screening must continue such as including length of diagnosis, type of diabetes, HbA1c (sugar level), blood pressure and blood fats so that the screening service can be optimized to reflect an individual’s risk.
Also Healthcare in the UK actually needs to increase patients’ awareness of the risks and impress on people the importance of bringing about wholesale changes in lifestyle, improving self-management and taking responsibility for their condition among people with diabetes and improve access to integrated diabetic care services.
In other words, prevention of diabetic eye disease is surely a better option than simply monitoring for the progression of eye disease. This should also be placed firmly back into diabetic care where for example foot checks, BMI, blood and urine tests are conducted at the same time as diabetic eye screening which are shown in some trials to reduce the number of appointments for the patient and release GPs to plan other forms of healthcare.
Perhaps we now have good enough evidence that advice from consultant ophthalmologists like Dr Elizabeth Wilkinson to diabetic eye patients regarding the fact that their high blood sugars were affecting the blood vessels at the back of the eyes causing them to leak and bleed and narrow and that images showing where the blood, fluid and fats had leaked into the macula have had a real impact on improving patients’ lifestyles and encouraged them to take greater control of their diabetes thus reducing the risk of further diabetes related complications in the eye.
6.6 Educating patients about glaucoma and increasing the chances of detection and early treatment with a New app
Professor David Crabb
Professor of Statistics and Vision Research
City University London
With an estimated over half a million people in the UK living with the condition of whom approx. 50% are undiagnosed – and affecting around around 66 million people worldwide – glaucoma describes a group of eye conditions that result in progressive damage to the optic nerve which connects the retina to the brain, causing people to gradually lose vision.
What makes glaucoma dangerous, however, is that this early vision loss can go undetected and as glaucoma worsens, these compensatory perceptive mechanisms unravel leading to noticeable sight loss, visual impairment and in some cases blindness. The condition is irreversible.
Against this background, researchers from City University London have developed a highly engaging new app, supported by Allergan Pharmaceuticals to educate people who have been newly diagnosed with glaucoma about the condition. What makes this app different is that this is glaucoma education in a simple, visual, jargon-free, easy to use format, which makes it more engaging and helps people better understand the potential impact of the condition. The app, designed for use on tablet devices covers topics such as why eye pressure is important as well as the correct use of eyedrops.
This app is one part of the ‘Glaucoma in Perspective’ programme, which comprises two apps – the second app, for Healthcare Professionals aims to facilitate and engage discussion and education of patients with the condition.
One of the main features of both apps is a series of interactive demonstrations that highlight the subtle sight loss that can occur with glaucoma, especially in the early stages of the disease. The app technology allows the user to experience the impact of glaucoma on everyday situations such as driving, cooking, walking down the stairs or shopping. Users are also provided with up-to-date information about their condition and the treatments available via a series of novel animations.
Professor Crabb and his team in collaboration with Dr Nicholas Smith, based the interactive app on findings from their research into patient’s perception of sight loss with glaucoma.
Professor Crabb said: “If you have glaucoma, or someone you know has glaucoma, this app has been developed for you. By working in partnership with Allergan we hope we can help raise awareness of glaucoma and explain why people invariably have no symptoms in the early stages of the disease. We have deliberately kept the app simple to use and easy to understand. We also hope the app will help clinicians better explain the benefits of adhering to treatment.”
The app is available free of charge on iTunes here and for health professionals here.
It is also available free of charge on Google Android here.
Our visual system contributes by far the greatest sensory input in our daily lives. In some surveys, the impact on quality of life due to the loss of vision has been equated to disseminated cancer, intractable pain and stroke.
This Report appears at a time when many causes of blindness are increasing worldwide due to ageing populations (affecting every person living a normal lifespan) leading to a huge unmet need. This has very significant implications for society in the decades to come.
From the eye research community’s point of view, the opportunities to make a significant difference to people’s lives have never been greater. This is a critical time when we can harness the revolution in biological sciences, engineering and computing to prevent and cure the causes of vision loss. It has never been more important to foster multi-disciplinary and collaborative working between researchers and clinicians. However, the realisation of human benefits from exciting laboratory work requires time and, above all, funds. Real hope is given to the visually impaired, blind and those not yet affected by sight loss by the continuing incremental progress driven by the expertise and commitment of academic researchers, clinician scientists and clinicians. They strive for positive clinical outcomes, supported by input from patients.
In the face of exponential growth in patient demand driven by an ageing population worldwide, eye research remains in an ideal position to support Ophthalmology as a specialty in changing and modernising the delivery of care. However, it requires effective logistics and patient flow management, as well as the adoption of initiatives to reduce pressure in the secondary care sector, to ensure that all intended consequences from eye research are optimised. Ophthalmology is a high volume specialty, accounting for more than 8% of all outpatients and 7% of all surgical activity. The combination of the increasing prevalence of ophthalmic disease in an aging population, the availability of new treatment and management guidelines, has increased demand for ophthalmology services without a matching increase in ophthalmic workforce or infrastructure support. Some organisations argue that this has greatly increased the risk of an unnecessary loss of vision due to failure to manage essential follow-up outpatient appointments effectively, in many cases due to prioritising new appointments over follow-ups.
This report attempts to highlight the complexity of eye research facing the multi-layered problem of sight loss. A wide range of contributory texts from leading researchers and clinicians based in the UK provide examples of the creative thinking and constant innovation stretched across a spectrum of research activities from cell biology to robotics. It gives examples of where research has already transformed the care of patients with previously untreatable blinding disease, such as wet macular degeneration. As exciting, it shows the huge translatable potential of eye research where other areas of eye disease could benefit. In addition, other areas of medical research such as cardiovascular disease, neurodegeneration, gene therapy, cancer and regenerative medicine could benefit greatly from the research into eye disease. It raises the profile of currently unavoidable sight loss alongside avoidable sight loss. It points to some of the rarer eye diseases, highlights the critical link between the brain and the eye, and makes the case for basic research in addition to the more obvious benefits of, for example, imaging technology. It acknowledges the critical role that patients can play in defining treatment priorities and influencing the provision and quality of eyecare.
The breadth and depth of eye research in 2017 is astonishing. It is now routine for practitioners, for example, to offer laser and cataract surgery, corneal transplantation, drug treatments for a range of diseases from wet AMD to glaucoma, less invasive and robotic assisted surgery, next generation sequencing, enhanced drug delivery and infection control, imaging supported by Artificial Intelligence (AI), retinal implants and intraocular lenses, low vision aids and so much more. In addition, research may begin to influence logistic issues that are very important to patients, such as the geographical location of clinics and hospitals, parking restrictions and transport improvements, with the advent of technologies such as portable multimodal imaging and data transfer and self driving transport. Research will continue to deliver improvements in the areas of prediction, detection, diagnosis, treatment, monitoring and rehabilitation. These have the potential to reduce the pressures in secondary care and widen capacity in primary care by educating practitioners and their patients. The promotion of individual responsibility and self-care, including reaching communities such as those with dementia and involving them in the process of detection and intervention, can restore mobility and social connectivity, and employment. This, in turn, will encourage greater patient input into the provision of eyecare, delivering “appropriate treatment at the appropriate time and in the appropriate place”.
Eye research has changed the lives of many millions of people around the world for the better. However, future research has the potential to change the lives of many many more. It is hoped that this report will stimulate and result in more of this life-changing research in the future.
Professor Sir Peng Tee Khaw
PhD FRCS FRCP FRCOphth FRCPath FRSB FCOptom Hon DSc FARVO FMedSci
NIHR Biomedical Research Centre Moorfields Eye Hospital and UCL Institute of Ophthalmology
Research and Development Moorfields Eye Hospital
Eyes and Vision Programme, UCL Partners Academic Health Science Centre
Julian Jackson wishes to thank all contributors for their unwavering support for this Report and their unflagging encouragement for the promotion of eye research across the UK.
To the best of the author’s knowledge, All titles and locations relating to contributors were accurate on the date of receipts of edited texts
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