Spinal muscular atrophy (SMA) is a neuromuscular disease caused by mutations in SMN1. The authors have previously demonstrated that CNS delivery of an AAV vector encoding SMN1 produced significant improvements in survival in a mouse model of SMA. Here, they performed a dose response study in SMA mice to determine the levels of SMN in the spinal cord necessary for efficacy, and measured the efficiency of motor neuron transduction in the spinal cord following intrathecal delivery in pigs and NHPs (nonhuman primates). CNS injections of 5e10, 1e10, and 1e9 genome copies (gc) of scAAV9-hSMN1 into SMA mice extended their survival from 14 to 153, 70, and 18 days, respectively. Spinal cords treated with 5e10, 1e10, and 1e9 gc showed 70-170%, 30-100%, and 10-20% of wild type levels of SMN were attained, respectively. Furthermore, detectable SMN expression in a minimum of 30% motor neurons correlated with efficacy. A comprehensive analysis showed that intrathecal delivery of 2.5e13 gc of scAAV9-GFP transduced 25-75% of the spinal cord motor neurons in NHPs. Thus, the extent of gene expression in motor neurons necessary to confer efficacy in SMA mice could be obtained in large animal models, justifying the continual development of gene therapy for SMA.
