Cone photoreceptor rescue in inherited retinal degenerations. (360G-Wellcome-086868_Z_08_Z)

This project is to investigate whether slowing cone photoreceptor loss could be used as a widely applicable treatment to preserve sight in inherited retinal degenerations. Neurotrophic factors, apoptosis inhibitors and transplanted rods have previously shown promise, but key questions remain: 1. Are initial rescue effects maintained over time, or subsequently lost by accelerated apoptosis? 2. Can cone cell rescue still be achieved once all rods have degenerated (a common clinical scenario)? 3. Could rods transplanted into the vitreous slow cone degeneration (the vitreous is a clinically attractive site for cell transplantation)? These questions will be addressed using adeno-associated viral (AAV) gene transfer to achieve sustained intraocular levels of a promising neurotrophic factor with a clinical safety profile (GDNF - delivered to inner retinal cells by AAV serotype 2) and cone selective expression of a potent intracellular inhibitor of apoptosis (XIAP - delivered to photo receptors by AAV serotype 5). In the third experiment rod progenitors will be isolated and transplanted into the vitreous cavity. All experiments will be performed in a novel mouse model of rod-cone degeneration in which the cones are genetically labelled with a fluorescent probe, allowing repeated anatomical and functional tracking of the degeneration over time.