CSF delivery of AAV9-mediated gene therapy for SMA, a lethal neuromuscular disease in children: a dose-response study in mice and nonhuman primates (P3.133)

Objective: Spinal muscular atrophy Type-1 (SMA1) is the most frequent lethal genetic neurodegenerative disorder in infants caused by low abundance of the survival of motor neuron (SMN) protein leading to motor neuron degeneration, progressive paralysis, and death. SMA1 symptoms are thought to be caused by death of motor neurons within the central nervous system. However, other non-central nervous system tissues may contribute to systemic disease symptoms in SMA1 patients that may not contribute to the milder phenotypes (SMA2-3). We previously demonstrated that a single intravenous injection (IV) of a gene therapy (AVχS-101) resulted in complete rescue of the disease phenotype in the SMA1 mouse model. Here, we evaluate the dosing and efficacy of AVχS-101 delivered directly to the cerebral spinal fluid (CSF) via single injection. Background: AVχS-101 delivers the SMN gene in a single-dose via the AAV9 viral vector (crosses blood-brain-barrier), utilizing self-complementary DNA technology for rapid onset transgene expression, and exploiting a chicken b-actin promoter for continuous and sustained transgene expression. Design/Methods: AVχS-101 was delivered via Intracerebroventricular (ICV) injection in the mouse model for SMA (SMND7 mouse) to evaluate phenotypic rescue. The scAAV9-Green Fluorescent Protein (scAAV9-GFP) was used to evaluate transgene/AAV9-biodistribution and was delivered via ICV injection in mice and intrathecal sacral infusion in cynomolgus macaques. Results: We found transgene expression throughout the spinal cord in mice and nonhuman primates. Moreover, the transduction efficacy is further improved when subjects are kept in the Trendelenburg position to facilitate vector distribution. Conclusions: CSF delivery of gene therapy utilizing the AAV9 viral vector combined with tilting (Trendelenburg position) allows widespread transgene transduction in the brain and all regions of the spinal cord of nonhuman primates. These findings support the use of IT delivery of gene therapy for neurological diseases, such as SMA 2 and 3 where there is minimal systemic involvement. Study Supported by: Aveχis, Inc. Disclosure: Dr. Meyer has nothing to disclose. Dr. Ferraiuolo has nothing to disclose. Dr. Nagendran has received personal compensation for activities with AveXis, Inc. Dr. Nagendran holds stock and/or stock options in AveXis, Inc. Dr. L9Italien has received personal compensation for activities with AveXis, Inc. Dr. L9Italien holds stock and/or stock options in AveXis, Inc. Dr. Sproule has received personal compensation for activities with AveXis, Inc. as an employee. Dr. Sproule hold stock and/or stock options with AveXis, Inc. Dr. Du has received personal compensation for activities with AveXis, Inc. as an employee. Dr. Du hold stock and/or stock options with AveXis, Inc. Dr. Cardenas has received personal compensation for activities with AveXis, Inc. as an employee. Dr. Cardenas holds stock and/or stock options in AveXis, Inc. Dr. Burghes has received personal compensation for activities with AveXis, Inc., Novartis and Guide Point as a consultant, or member of the advisory board. Dr. Foust has received personal compensation for activities with AveXis, Inc. as an employee. Dr. Foust has received licensing fees from AveXis, Inc. Dr. Foust has received stock and/or stock options with AveXis, Inc. Dr. Kaspar has received personal compensation for activities with AveXis, Inc as an employee. Dr. Kaspar holds stock and/or stock options in AveXis, Inc. Dr. Likhite has nothing to disclose. Dr. Mendell has received personal compensation for activities with AveXis, Inc. and Sarepta Therapeutics as a consultant. Dr. Mendell has received research support from Sarepta Therapeutics Inc. and AveXis, Inc. Dr. Kaspar has received personal compensation for activities with AveXis, Inc as an employee.