Our research 2018 funded research Dr Mariya Moosajee - University College London Preventing photoreceoptor cell death in retinal dystrophies by regulating glucose metabolism in the retina The retina is the light-sensing layer at the back of the eye that converts light into chemicalsignals that pass to the brain to help us to see. There exists a group of eye conditions thatspecifically affect the retina called inherited retinal diseases (IRD), which are caused byabnormal changes (also known as mutations) in our genetic code. IRD are the most commoncause of blindness in working age adults in England and Wales, and the second commonestin childhood. Currently, there is no cure or specific treatment available to patients. There arecurrently ~250 genes, that if mutated, cause IRD, so developing a gene therapy for each wouldbe extremely challenging, time-consuming and costly. The retina is made up of several layersof cells; the light-sensing cells are called photoreceptors. Degeneration of photoreceptors iscentral to visual impairment arising from most IRD. Recent advances in the understanding ofthe mechanisms of photoreceptor death have emphasized the role of failure of energyproduction (metabolism), and in particular, a failure of sugar (glucose) uptake intophotoreceptors, which is used to produce energy. In this proposal, we seek to test the hypothesis that enhancing photoreceptor energyproduction can prevent or slow cell death, and therefore, lead to the development of a universaltreatment for IRD regardless of their genetic basis. We will use two human equivalent zebrafishIRD models, which show a rapid retinal degeneration caused by changes in the RPGR andPDE6C gene. We will enhance glucose uptake and utilization by increasing the number ofglucose transporters into cells and related metabolic enzymes, which increase energyproduction. To assess glucose uptake into the retina, we will label glucose with a fluorescenttag to provide a direct measure. The impact of these interventions on photoreceptor metabolism will be assessed usingexperiments to measure the amount of energy molecules produced, oxygen usage, andpatterns of gene function. Photoreceptor survival will be assessed by investigating thestructure of the treated retina, measuring levels of cell death and testing the vision of thezebrafish. If successful, further funding or partnership with industry will be sought to develop a genetherapy using the most efficient candidate to enhance glucose uptake or metabolism. Thisproject has the potential to prevent, halt or slow retinal degeneration by enhancing energyproduction in a vast number of patients with incurable blinding disease.