Inherited retinal degenerative diseases (RDDs) are a heterogeneous group of disorders that constitute a major cause of vision loss in the world population. In most cases, they are caused by mutations in genes that encode proteins essential for photoreceptor cell structure, function and survival. Although significant progress has been made in the genetics of RDDs, mechanisms by which various genetic defects cause photoreceptor degeneration and a loss in vision are not well understood. The objective of this application is to increase our understanding of the molecular and cellular mechanisms underlying two severe early onset disorders, Stargardt macular degeneration associated with mutations in the retinoid transporter ABCA4 and Leber Congenital Amaurosis Type 12 (LCA12) linked to mutations in RD3, a novel protein essential for guanylate cyclase expression in photoreceptor cells. This information will be used to test the hypothesis that novel therapeutic treatments can be developed in animal models for these diseases as an essential step for translation into human clinical trials.
Three specific aims of this application are: 1) To examine the structural, functional and regulatory properties of ABCA4 and identify novel nontoxic chemical compounds that enhance the retinoid transport activities of WT and Stargardt disease-causing mutants of ABCA4 and hence serve as potential therapeutic drugs; 2) to further evaluate the therapeutic potential of selected drug compounds in animal models for Stargardt disease; and 3) to investigate the mechanisms underlying the function of RD3 in guanylate cyclase expression and trafficking in photoreceptors and evaluate adeno-associated viral (AAV) vectors for the delivery and expression of RD3 and the rescue of rod and cone function and survival in the rd3 mouse model for LCA12.
These aims will be achieved by using newly developed in vitro retinoid transport assays, established and newly generated animal models, in vivo and in vitro imaging methods, protein expression and purification, novel viral gene delivery vectors, and high throughput drug screening methods. The results of this research will yield novel insight into the structure and function of ABCA4 and RD3 in rod and cone photoreceptor cells and further define how mutations in these proteins cause photoreceptor degeneration in Stargardt disease, LCA12, and related diseases. Importantly, this work will provide a 'proof of concept' that novel drug and gene based treatments can be developed for translation into future clinical trials for these diseases. These studies will also have a strong impact in other biomedical research. The knowledge gained from our studies of ABCA4 and Stargardt disease will enhance our understanding and treatment of other diseases (cystic fibrosis, Tangiers disease, adrenoleukodystrophy, etc.) linked to genetic defects in related ABC transporters and the studies on RD3 and LCA12 will extend our understanding of protein expression and trafficking and AAV-mediated gene therapy for the treatment of various diseases.
Stargardt macular degeneration and Leber Congenital Amaurosis Type 12 are early onset retinal degenerative diseases which cause severe vision loss in the world population. Although the genetic defects responsible for these disorders have been identified, the molecular and cellular basis for how these defects cause vision loss is poorly understood and therapeutic treatments are not available. The current application will enhance our understanding of the mechanisms underlying Stargardt disease and Leber Congenital Amaurosis Type 12 and develop novel drug and gene delivery - based treatments which can prevent or slow vision loss in animal models as an essential step for future clinical trials.
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