Event Review: Shining a Light on Genetic Disorders – Genetic eye disorders

As a post-2020 cynic, online events can often seem daunting and the last place I expected to feel an endearing sense of community was a Zoom call. The Institute of Genetics and Cancer at the University of Edinburgh virtually hosted their seventh genetic eye disease conference in June 2021, connecting geneticists, clinicians and researchers from the Medical Research Council Human Genetics Unit (MRC HGU). The panel reviewed advances in our understanding of genetic eye disease, while also featuring patient voices which reinforced the impact of medical research. Not only was the event enlightening but, as a Scottish expat, it was refreshing to hear familiar intonations.

With a deadpan levity you cannot help but admire, the event was compered by Glaswegian comedian Jamie MacDonald, whose routine involves his experience living with retinitis pigmentosa (RP) – a degenerative eye condition caused by a mutation in over 100 potential genes. Although the events of the past year may disagree, there's nothing more infectious than laughter and the compere set a joyful yet earnest precedent for the event.

Initially, Denise Rawden and Kate Arkell presented an update from Retina UK, an organisation helping those with inherited sight loss. In a public survey conducted by Retina UK, 43 percent of people were unaware of genetic testing for eye disease or that this resource was readily available. Funded by Novartis, Retina UK have thus refreshed their website to provide accessible information covering topics such as genetic inheritance patterns, GP referrals, genetic testing and counselling services. The redesign looks extremely user-friendly, aiming to simplify the diagnostic process and educate the public in concert with the Retina UK podcast.

Transitioning into research, Dr Roly Megaw, clinical researcher at the MRC HGU, described the process of generating 'mini eyes' in the lab – a technique which sounds straight out of an HG Wells novel. Using stem cells from RP patients, researchers dictated cellular fate with a chemical cocktail to create eye-like organoids with bona fide photoreceptors (specialised cells which convert light into electrical signals). Compared to eyes from healthy controls, RP photoreceptors expressed more actin – a protein involved in maintaining cellular structure. As discussed in a recent review, this indicates that actin dysregulation is associated with degeneration of retinal photoreceptors. Regardless, the use of these 'mini eyes' is clear and makes you question what is actually possible in the realm of science fiction.

Therapeutic advances for eye disease were also considered: Dr Megaw noted the ongoing BRILLIANCE clinical trial for retinal dystrophy – the first therapy to use the CRISPR approach to genome editing in living humans. Encouraging results from genome editing have already been seen for RP (see BioNews 1097), including visual improvement in X-linked RP patients during a phase I/II trial run by MeiraGTx. Recruitment for the phase III trial, using the drug AAV-RPGR, is ongoing and Dr Megaw's passion was evident as he encouraged patients to volunteer.

In addition to stem cell models, Dr Shipra Bhatia, research fellow at the MRC HGU, summarised the use of zebrafish in studying aniridia – a condition involving complete or partial absence of the iris. Mutations in the PAX6 gene are a major cause of aniridia and Dr Bhatia replicates this in the zebrafish genome. Using fluorescent tags to monitor the PAX6 protein (the fish are entirely transparent!), the effects on expression can be observed. Changes in protein structure can also be computationally modelled, as outlined by Dr Joseph Marsh, research group leader at MRC HGU. For instance, the I42S mutation in PAX6 was shown to produce a hole in the folded protein, likely leading to loss of function. As someone with a basic understanding of Microsoft Excel, the capabilities of computational modelling were certainly impressive.

Genetic mutations leading to inherited eye disease are often discovered through the use of Genome-wide association study (GWAS). Essentially, this compares genes between affected and unaffected individuals to identify common variants within each group. This is the case for ZNF469, which is mutated in Brittle Cornea Syndrome. Dr Chloe Stanton, research fellow at the MRC HGU, explained how disrupting ZNF469 expression in mice reduced the thickness of the cornea by approximately 30 percent, mainly in the fibrous stroma layer. Disease-associated ZNF469 variants identified by GWAS are currently being followed up in the lab to monitor the effects on expression or function.

The highlight of the evening was the musings of Ken Reid, who recounted how an RP diagnosis changed his life. To an enraptured audience, Reid described how he stopped being able to watch his daughter grow up and, due to his deteriorating vision, was forced to retire at 48 years old. However, he stated that his diagnosis was 'a life sentence, not a death sentence'. Through his involvement in RP awareness campaigning, Reid has served as chair of the Royal National Institute of Blind People Scotland and was a torchbearer in the 2012 Olympic relay.

Too often, the dissociation between the laboratory environment and the realities of disease can allow you to forget the importance of research. Particularly after the past year, it was heartening to see a passionate and friendly community, albeit virtually, which assured me the future of genetic eye disease research indeed looks bright.