Grant: Operating Grant

Can normal vision be restored to animal models of CSNB? Mutations in more than 180 human genes are known to be cause heritable retinal diseases that often lead to blindness. The gene called CACNA1F produces a protein that mediates the entry of calcium into photoreceptor cells in the retina, which is essential for transmission of visual signals from rods and cones to the brain. Mutations in CACNA1F cause a disease called congenital stationary night blindness (CSNB), in which patients have impaired night vision, short-sightedness (myopia), and a substantial loss of visual acuity that cannot be corrected. The major focus of our research is to determine whether photoreceptors can be made to establish functioning synaptic connections after they have failed to form during the normal period of retinal development. In studying the retina of a novel mutant mouse (G305X-CSNB) that models or mimics CSNB, we found that rod and cone photoreceptors fail to form the synaptic connections needed for sending visual signals to other retinal nerve cells. This failure causes the remaining cells in the retina to undergo characteristic changes and rearrangements. Such cellular remodeling is also observed in many other retinal diseases including retinal detachments. We want to know whether we can reverse these abnormal retinal features and restore normal function to the CSNB retina. This problem will be investigated using a genetic-engineering approach and by transferring a normal calcium channel gene (CACNA1F) into the retina of G305X-CSNB mice. Our research involves far-reaching collaborative efforts that will bring together the required expertise for achieving our research goals. Establishing that rod and cone photoreceptors can make functional synapses after long-standing retinal disease or injury will further encourage the development of therapeutic strategies for human retinal diseases.