Gene Therapy Approaches for Neurological Lysosomal Storage Diseases
Type of Degreedissertation
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GM1 and GM2 gangliosidosis are lysosomal storage diseases caused by deficiency of enzymes required for ganglioside catabolism. Enzyme deficiencies cause neuronal accumulation of ganglioside resulting in progressive neurodegeneration and premature death. There is no cure for these fatal diseases. Feline GM1 and GM2 gangliosidosis models are close replicas of the human juvenile- and infantile- onset disease forms, respectively, and provide ideal large animal models to test therapies for translation to humans. Prior to the initiation of this research project evaluating adeno-associated virus (AAV) gene therapy, no experimental treatment had altered the course of the feline gangliosidoses. Sixteen weeks after intracranial injection of AAV vectors in gangliosidosis cats, therapeutic enzyme activity was widely restored at near or above normal levels throughout the central and peripheral nervous system, and was also detected at lower levels in peripheral tissues. Restoration of enzyme activity resulted in substantial clearance of pathologic storage material and normalization of a secondary biomarker of lysosomal function. In long term treatment groups, mean survival of GM1 gangliosidosis cats treated before disease onset currently stands at >4.7 times that of untreated cats. The majority of treated cats remain alive and in good clinical condition, so mean survival continues to increase. Mean survival of GM2 gangliosidosis cats treated before disease onset was >4.3 times that of untreated. Enzyme activity was maintained throughout the current life span, but it was variable between subjects and between central nervous system regions, with several regions still demonstrating a substantial burden of storage material. The significant increase in life span of treated GM2 gangliosidosis cats resulted in the emergence of previously subclinical peripheral disease symptoms that were the ultimate cause of death in seven out of nine cats. AAV-gene therapy also produced significant survival gains in GM2 gangliosidosis cats treated during the early symptomatic disease stage, which is when most human patients are diagnosed. This research represents a significant advancement in the treatment of the feline gangliosidoses and supports the continued improvement and refinement of AAV gene therapy for translation to humans. Future studies should continue to investigate ways to maximize enzyme distribution throughout the central nervous system in order to further reduce storage material as well as investigate methods to treat peripheral disease pathology.