1.3 The importance of earlier interventions and alternative treatments – John Greenwood

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The importance of earlier interventions and alternative treatments
John Greenwood PhD FRCPath
Hugh Davson Professor of Biomedical Research Head of Department of Cell Biology
UCL Institute of Ophthalmology
University College London
Despite enormous progress in recent years in treating eye disease there remains an urgent clinical need for new therapies, especially those that intervene early in the disease process. Therefore, the aim of earlier intervention is that the disease can be halted or slowed down before it causes significant retinal damage and sight loss. This could occur before the need for anti-VEGF treatment or probably more likely in conjunction with anti- VEGF. New therapies that hit completely different targets may also be effective in anti- VEGF non-responders.
So, in response to this growing clinical need, the evidence emerging from the Greenwood and Moss laboratories at UCL Institute of Ophthalmology suggests that a new treatment may be able to target early disease changes that precede more obvious and macroscopic manifestations of a disease (gross pathology). For many years, they have been working to identify the fundamental causes of retinal disease with the aim of identifying new therapeutic targets. This work has led to the discovery of a molecule that plays an important role in promoting the growth of unwanted diseased blood vessels and that can be targeted therapeutically.
The uncontrolled growth of highly abnormal blood vessels is a feature of a number of sight-threatening diseases including wet age-related macular degeneration, proliferative diabetic retinopathy and retinopathy of prematurity. It is also a characteristic of life- threatening conditions such as cancer and atherosclerosis (clogging of arteries with fat deposits leading to hardening of arteries and then possibly 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.

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