iPSC modelling and multi-omics analysis to understand age-related macular degeneration

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Age-related macular degeneration (AMD) is a leading global cause of blindness that affects 8-12% of people over the age of 60 years. It is estimated that by the year 2040, 288 million people will be affected by AMD. As such, it represents one of the biggest economic burdens faced by healthcare services around the world. AMD is a complex condition, caused by a combination of non-modifiable (e.g. increasing age, ethnicity) and modifiable (e.g. obesity, smoking, dietary antioxidant intake) risk factors. Genetic variants also play a significant role in AMD risk, with rare and common polymorphisms in the Complement factor H (CFH) gene accountable for up to 50% increased risk of disease development. Animal and cellular models of AMD are not able to accurately replicate the biological complexities of the condition, thus precluding understanding of the contribution of genetic variants to disease pathogenesis. Consequently, there are very few treatment options available. Early-onset macular degeneration (EOMD) is an important cause of severe and progressive visual loss in young adults that shows very similar disease pathology to AMD. Unlike AMD, EOMD has a much weaker association with life-style related risk factors and is often present in more than one generation of a family suggesting a strong genetic component. Research has shown that rare, deleterious and common AMD-associated DNA changes in the CFH gene underlie EOMD in a proportion of cases. The aim of this project is to study the role of CFH impacting variants disease pathogenesis using induced pluripotent stem cells (iPSC) differentiated in to retinal pigment epithelium (RPE) from EOMD patients. This study will investigate the direct impact of genetic variation on protein function, before employing cutting-edge 'omics methodologies to measure the genome-wide effect of impaired protein function at multiple biological levels. Increased understanding of EOMD biology will shed light on the mechanisms driving AMD onset and progression, and will facilitate the development of treatment strategies. In addition, further insight into the the contribution of genetic variants to disease development will provide more patients and their families with specialised care, precise diagnosis, prognostic information and genetic counselling- crucial in the era of personalised genomic medicine.