Research Summary

Development of a highly efficient and immunologically inert adeno-associated virus based vector system for retinal gene therapy

Leber congenital amarousis (LCA) type 2 is a form of hereditary blindness caused by mutations in the retinal pigmental epithelium (RPE) 65 gene. The disease is characterized by degeneration of the retinal cells and a progressive loss of photoreceptors leading to a profound impairment in visual function. LCA2 is an ideal target for gene therapy, since the molecular genetics and function of the RPE65 gene is well understood and there are several animal models, in which the novel therapies can be tested. However, recent data from clinical trials for LCA2 using AAV vectors demonstrate a significant loss in the photoreceptor activity and vision. This is due to either suboptimal delivery of the vector, a very low level expression of the transgene (RPE65) and the immune response directed against the vectors.  These observations underscore the need to decipher the molecular basis of immediate and long-lived target host cell response to the process of viral infection. The insights gained from such studies will help in designing (1) high transduction and permeating vectors that are amenable to less invasive ocular delivery procedures (2) vectors with improved efficiency in seropositive settings and (3) immunologically naive vectors that will permit their re-administration to augment visual function in the recipient. Our studies are planned to optimize some of these features within AAV based vectors. Such a multi-pronged approach encompassing the basic biology of the virus with specific efforts directed at minimizing its immunotoxicity and their pre-clinical validation in a retinal degeneration disease model of LCA, augurs well for their potential application in humans.

Figure Legend: Gene therapy for Leber congenital amarousis (LCA) type 2: A) Mutations in the RPE65 gene lead to a LCA2 phenotype with prominent degeneration of the retinal pigmental epithelial (RPE) cells. B) Gene therapy i.e, replacement of the defective RPE65 gene with a normal copy, using a delivery vehicle such as AAV has not been long-lasting in humans. We propose to develop newer vectors that can bypass some of these transduction and immune barriers, and further test them in suitable in vitro and in vivo models of LCA2.
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