Gene therapy for preserving the visual system in lysosomal storage diseases

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PROJECT SUMMARY The primary objective of the proposed research is to evaluate the safety and efficacy of AAV- mediated gene therapy for preventing the progressive retinal and central nervous system (CNS) degeneration in a canine model of CLN2 neuronal ceroid lipofuscinosis (NCL), particularly as they relate to functional vision. CLN2 disease results from deficiency of the soluble lysosomal enzyme tripeptidyl peptidase-1 (TPP1) caused by mutations in TPP1. Dachshunds with a null mutation in TPP1 were used in preclinical studies that supported development of CNS enzyme replacement therapy (ERT) that has been successful in preserving neurological function in affected children. Unfortunately, this treatment does not prevent retinal degeneration or the resulting blindness in CLN2 disease. In addition, ERT treatments require long clinic-bases intracerebroventricular injections every other week for life. Using the dog model, studies will be conducted to test the hypothesis that combined one-time intravitreal and intra-cerebrospinal fluid administration of AAV- TPP1 gene therapy vectors will prevent retinal degeneration and degeneration of the visual centers of the CNS and preserve functional vision, setting the stage for testing this treatment in children with CLN2 disease.