Degenerative diseases of the retina are responsible for devastating visual handicap affecting millions of individuals worldwide. Monogenic disorders with relatively early age-of-onset have been mapped to over 200 genetic loci. The discovery of mutations in the vitamin A visual cycle opened a path to the first successful clinical trials of therapies targeted to a specific genetic cause of retinal degeneration (RD). In individuals with mutations in the retinoid isomerase gene RPE65, compelling outcomes were obtained using gene therapy approaches that increase retina levels of the chromophore 11-cis retinal (11cRAL). However, such strategies are currently limited to the treatment of mutations resulting in visual cycle loss-of-function. Thus, there is an urgent need to find treatments for additional RD genotypes. Our interest is to determine the feasibility of expanding the use of chromophore supplementation for the treatment of genetically diverse forms of RD. Although in some circumstances increased levels of chromophore are associated with increased risk of light damage and lipofuscin accumulation, it is important to fully recognize the complex role of 11cRAL in the retina. 11cRAL is essential not only for initiating the visual response, but also serves as a powerful chaperone needed to stabilize the structures of the visual pigments. Deficits in 11cRAL production or availability impede the folding, trafficking and stability of rhodopsin and cone opsins, thereby contributing to programmed cell death, particularly affecting the cone cells. This profound dependence suggests that increasing chromophore may be useful for treating relevant RD phenotypes caused by a range of primary defects.
The specific aims of our proposal will test the hypothesis that increase in chromophore levels can diminish the disease phenotype of rat and mouse models of human RD caused by mutations affecting visual pigment function, visual cycle efficiency, and the photoreceptor membrane microenvironment. Our experiments will involve increasing chromophore levels by systemic delivery of retinoid, and by subretinal injection of viral vectors, in studies that will compare in vivo outcomes in phenotypes that are likely, or unlikely, to respond to treatment. The results of our study will provide critical insight into the effectiveness of currently available technologies for treating an expanded range of RD genotypes, and thus the possibilities for offering therapy to greater numbers of affected individuals in the near future.
The vitamin A analog 11cRAL is essential for maintaining the function and viability of the rod and cone photoreceptor cells. Strategies that supplement 11cRAL levels in the retina have proven effective for treating certain forms of inherited retinal degeneration caused by mutations in genes necessary for 11cRAL synthesis. Our interest is to obtain the supporting data needed to apply this strategy more broadly to the treatment of genetically diverse forms of retinal degeneration, with the long-term goal of increasing the number of patients who may benefit from this approach.