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 chemical
signals that pass to the brain to help us to see. There exists a group of eye conditions that
specifically affect the retina called inherited retinal diseases (IRD), which are caused by
abnormal changes (also known as mutations) in our genetic code. IRD are the most common
cause of blindness in working age adults in England and Wales, and the second commonest
in childhood. Currently, there is no cure or specific treatment available to patients. There are
currently ~250 genes, that if mutated, cause IRD, so developing a gene therapy for each would
be extremely challenging, time-consuming and costly. The retina is made up of several layers
of cells; the light-sensing cells are called photoreceptors. Degeneration of photoreceptors is
central to visual impairment arising from most IRD. Recent advances in the understanding of
the mechanisms of photoreceptor death have emphasized the role of failure of energy
production (metabolism), and in particular, a failure of sugar (glucose) uptake into
photoreceptors, which is used to produce energy.


In this proposal, we seek to test the hypothesis that enhancing photoreceptor energy
production can prevent or slow cell death, and therefore, lead to the development of a universal
treatment for IRD regardless of their genetic basis. We will use two human equivalent zebrafish
IRD models, which show a rapid retinal degeneration caused by changes in the RPGR and
PDE6C gene. We will enhance glucose uptake and utilization by increasing the number of
glucose transporters into cells and related metabolic enzymes, which increase energy
production. To assess glucose uptake into the retina, we will label glucose with a fluorescent
tag to provide a direct measure.


The impact of these interventions on photoreceptor metabolism will be assessed using
experiments to measure the amount of energy molecules produced, oxygen usage, and
patterns of gene function. Photoreceptor survival will be assessed by investigating the
structure of the treated retina, measuring levels of cell death and testing the vision of the
zebrafish.


If successful, further funding or partnership with industry will be sought to develop a gene
therapy using the most efficient candidate to enhance glucose uptake or metabolism. This
project has the potential to prevent, halt or slow retinal degeneration by enhancing energy
production in a vast number of patients with incurable blinding disease.