Translational Fidelity of Intrathecal Delivery of Self-Complementary AAV9–Survival Motor Neuron 1 for Spinal Muscular Atrophy

Abstract

Spinal muscular atrophy (SMA) is a neuromuscular disease caused by mutations in survival motor neuron 1 (SMN1). Previously, we showed that central nervous system (CNS) delivery of an adeno-associated viral (AAV) vector encoding SMN1 produced significant improvements in survival in a mouse model of SMA. Here, we 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 after intrathecal delivery in pigs and nonhuman primates (NHPs). CNS injections of 5e10, 1e10, and 1e9 genome copies (gc) of self-complementary AAV9 (scAAV9)-hSMN1 into SMA mice extended their survival from 17 to 153, 70, and 18 days, respectively. Spinal cords treated with 5e10, 1e10, and 1e9 gc showed that 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.

Gaucher-related synucleinopathies: The examination of sporadic neurodegeneration from a rare (disease) angle

“…Although initial indications from these studies are encouraging, it is evident that second-generation vectors that exhibit a greater safety profile and transduction activity may be required before this optimism can be fully realized (Cheng, 2014). Several recent studies have suggested that some AAV serotypes could achieve extensive CNS distribution in non-human primates (Passini et al, 2014;Yang et al, 2014a). However, the optimal serotype, route of delivery and brain distribution to critical brain regions must be further investigated prior to the development of glucocerebrosidase gene therapy for conditions requiring widespread distribution of therapeutic proteins in the CNS, including lysosomal storage diseases and Gaucher-related PD.…”

Improving Single Injection CSF Delivery of AAV9-mediated Gene Therapy for SMA: A Dose–response Study in Mice and Nonhuman Primates

“…Several studies quantified transduction levels and patterns in brain and spinal cord of mice after CSF and IV delivery of AAV [24][25][26][27][28][29] . The use of different injection strategies, AAV serotypes, as well as dosing led to variable results in pigs and nonhuman primates 21,24,[30][31][32][33][34] .…”

How far away is spinal muscular atrophy gene therapy?

“…Contemporary studies confirmed the benefits of intravenous scAAV9-SMN1 delivery in P1 SMA mice, and also demonstrated remarkable protection following CNS and intramuscular delivery [5][6][7]. Importantly, the therapeutic relevance of this approach has been demonstrated by successful systemic or intrathecal delivery of viral vectors carrying a green fluorescent protein into juvenile pigs and primates, resulting in robust expression [4,8,9]. Indeed, intrathecal delivery of scAAV9 carrying human SMN1 conferred significant benefit to a pig model of SMA [10].…”