Stemming the cascade, understanding genetics factors behind retinal diseases

Retinal diseases are severe and debilitating with potentially devastating effects on a person’s vision and quality of life.  At Roche we’re following the science to develop new medicines for a range of eye diseases, and our ophthalmology research projects focus on age related macular degeneration (AMD), diabetic macular oedema, diabetic retinopathy, geographic atrophy (GA) and glaucoma. Jason Ehrlich, Menno van Lookeren Campagne and Brian Yaspan from the Ophthalmology Research and Development teams provide their individual insights into the significance of understanding genetic factors behind retinal diseases, and how this can drive research in the identification of new therapeutic targets.

What is exciting about the research landscape today in retinal disease?

[Jason] Many companies and academic centres are increasingly pursuing the development of impactful therapies in retinal disease, including conditions with limited or no treatment options – for example, GA is an advanced form of AMD that affects over 5 million people globally in the developed world, yet is still currently untreatable with no approved therapy.

Over the next decade, insights from human genetics and advances in the technology of drug development will hopefully result in bringing innovative therapies to people with vision-threatening diseases – for example, exciting research is ongoing looking at different therapeutic options for neovascular AMD, diabetic eye disease, and glaucoma; as well as development of technologies that aim to sustain treatment effect for longer periods of time.

Why is it important to understand the genetics of a disease?

[Brian] Identifying genetic drivers is crucial for a complete understanding of the underlying disease architecture. Not only can genetic analyses identify factors of disease risk, they can also shed light on disease severity and progression. Currently there are more than 30 genetic loci associated with AMD identified from genome-wide association studies.  This information, coupled with data collected from family members of people with AMD, help scientists better characterise the biological pathways involved in AMD development.  For example, genetic factors linked to lipid metabolism, cell death (apoptosis) and growth of new blood vessels (angiogenesis) have been identified.  One of the newer areas of research in ophthalmology involves the complement system, a complex area with many groups investigating different approaches.

What is the complement system and why is it an attractive target for development of treatments against retinal diseases?

[Menno] The complement system is part of the body’s natural immune system, designed to help fight pathogens or cancer cells.  It consists of a number of proteins in the blood – called complement factors – that work together in a cascade to initiate and amplify an immune response to pathogens and altered cells. This cascade is tightly regulated by inhibitors that prevent uncontrolled amplification of the pathway. In diseases such as AMD and GA the regulation of the complement system is malfunctioning, leading to inflammation and damage to the cells of the retina.

Finding a way to prevent or decrease complement activation in people with certain eye disorders is essential to prevent the progression of retinal cell degeneration.”

Think of the complement system as a cascading mountain river: early complement activation is harmless – like the small stream at the top of the mountain.  Further down the mountain and in the presence of a heavy storm, these merging streams cause uncontrolled flooding and damage – this is what happens when the amplification of the complement pathway is uncontrolled.

By gaining a thorough understanding of how complement activation is initiated, one has the possibility of developing smart complement inhibitors to block critical components upstream in the pathway. Today we know of genetic variants, called polymorphisms, which alter the functionality or expression level of critical inhibitors of the complement system such as CFH and CFI.  This genetic variation can help us identify sub-populations of patients that may benefit from specific complement therapeutics to block or slow retinal cell degeneration.

What motivates you personally and professionally in your role?

[Jason] I trained both as an ophthalmologist and cell biologist. What excites me most is the opportunity to have a broad and meaningful impact on patients' lives. At Genentech and Roche, I am fortunate to have colleagues who are all true experts in their fields - from human genetics to trial operations, manufacturing, or biostatistics - and by gathering those experts together in partnership we all have a unique chance to work on therapies that can make a tremendous difference. Not only is the scientific environment here exciting to be a part of, but the impact we can have on people’s lives is truly profound. It's this shared sense of purpose around helping people living with vision-threatening disease that motivates me every day.

Tags: Ophthalmology, Geographic Atrophy, AMD