Phase II Study of AAV9-GAA Gene Transfer in Pompe Disease

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 DESCRIPTION (provided by applicant): The long-term goal of this proposal is to investigate the efficacy of systemic dosing of adeno associated virus (AAV) serotype 9 vector to correct cardiorespiratory insufficiency and skeletal muscle weakness in Pompe disease. Pompe disease results from a deficiency or absence of the lysosomal enzyme acid alpha glucosidase (GAA), and in result, glycogen accumulation impedes cardiac, respiratory and neuromuscular function. Respiratory failure is the leading cause of morbidity and mortality in Pompe patients. AAV vectors for gene therapy are currently under phase I/II clinical trials for multiple inherited conditions, including our ongoing intramuscular administration to the diaphragm of rAAV1-CMV-hGAA in ventilator-dependent pediatric Pompe patients. In this project, we propose to build upon experience from this recent trial, to incorporate innovative, mechanistic outcome measures, and to advance the therapeutic approach with a novel delivery method and advanced serotype (AAV9). The central hypothesis is that restoration of GAA activity in muscle and neural tissue is safe and will reverse cardio-ventilatory insufficiency and skeletal muscle weakness in children with Pompe disease. We propose to utilize cutting-edge imaging and electrophysiological modalities to characterize mechanisms of vector action. In addition, we have developed innovative manufacturing techniques for a therapeutic AAV construct with improved transduction to neural tissue, tissue-specific desmin promoter, and codon-optimized GAA cDNA. Based upon strong preliminary data, this proposal will test two specific aims: Aim 1. Determine the safety and the retrograde neuro-transduction of systemic rAAV9-DES-hGAA dosing in infant rhesus monkeys (done concurrently with other IND-enabling primate studies). Aim 2. Evaluate the safety and efficacy of systemic rAAV9-hGAA in children with early-onset Pompe disease. This proposal will significantly advance the field in three major areas: (1) elucidate the safety o AAV9 systemic delivery; (2) treatment of the neural as well as the muscular components of weakness in Pompe disease; and (3) investigate the utility of imaging and neurophysiological tests as biomarkers of cardiorespiratory and skeletal muscle function.