Whole-body therapy for GM2 gangliosidoses

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 DESCRIPTION (provided by applicant): Lysosomal storage diseases consist of >40 distinct disorders, each having an underlying defect in lysosomal function that leads to storage of normally degraded substrates. Lysosomal diseases have a cumulative prevalence of 1 in 7,700 live births, similar in frequency to cystic fibrosis and hemophilia. All lysosomal storage diseases affect peripheral organs to some degree, and the majority also attack the central nervous system (CNS). Though effective treatments have been developed for peripheral manifestations of some lysosomal diseases, those with neurological components have been virtually untreatable. A new therapeutic era is at hand for lysosomal storage diseases with neurological involvement. Intracranial injection of adeno-associated viral (AAV) vectors has led to > 4-fold increases in life span and vastly improved quality of life in mice and cats with Sandhoff disease, a type of GM2 gangliosidosis caused by a lack of the enzyme hexosaminidase. In fact, AAV vectors address the central nervous system disease component so successfully that peripheral disease becomes the primary barrier to long-term survival. A second barrier to successful clinical application in humans is the risk of directly injecting the brain, especially in children ith progressive neurologic disease. The current proposal will minimize risk and optimize vector delivery to the brain, spinal cord and peripheral organs to treat CNS and peripheral disease simultaneously. Aims include the following: (1) Optimize treatment of the brain and spinal cord by injection of AAV into the cerebrospinal fluid. Peripheral effect also will be tested, but the primary goal of Aim 1 is treatment of the CNS. (2) Treat peripheral organs by intravascular delivery of AAV. Effect in the brain and spinal cord also will be measured, but the primary goal of Aim 2 is treatment of the periphery. (3) Evaluate whole-body AAV therapy through simultaneous application of cerebrospinal fluid and intravascular approaches. This project will investigate a new AAV capsid that transduces the brain at high efficiency, a bicistronic vector that expresses both subunits of hexosaminidase from a single construct, a combination of treatment approaches not previously reported and clinical assays such as echocardiography and magnetic resonance imaging/ spectroscopy at high field strength (7 Tesla). Conclusions from this project will inform future human clinical trials for GM2 gangliosidosis.