title: 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.
authors.affiliation: 1 Rare Diseases Science, Genzyme, a Sanofi Company , Framingham, MA 01701.
authors.forename: Marco A
authors.initials: MA
authors.lastname: Passini
authors.forename: Jie
authors.initials: J
authors.lastname: Bu
authors.forename: Amy M
authors.initials: AM
authors.lastname: Richards
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Treleaven
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Sullivan
authors.forename: Catherine R
authors.initials: CR
authors.lastname: O'Riordan
authors.forename: Abraham
authors.initials: A
authors.lastname: Scaria
authors.forename: Adrian P
authors.initials: AP
authors.lastname: Kells
authors.forename: Lluis
authors.initials: L
authors.lastname: Samaranch
authors.forename: Waldy
authors.initials: W
authors.lastname: San Sebastian
authors.forename: Thais
authors.initials: T
authors.lastname: Federici
authors.forename: Massimo S
authors.initials: MS
authors.lastname: Fiandaca
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Boulis
authors.forename: Krystof S
authors.initials: KS
authors.lastname: Bankiewicz
authors.forename: Lamya S
authors.initials: LS
authors.lastname: Shihabuddin
authors.forename: Seng H
authors.initials: SH
authors.lastname: Cheng
mesh_terms: D000818:Animals; D000229:Dependovirus; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D007278:Injections, Spinal; D051379:Mice; D018345:Mice, Knockout; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology; D009134:Muscular Atrophy, Spinal / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D014176:Protein Biosynthesis; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D055533:Survival of Motor Neuron 1 Protein / Q000096:biosynthesis / Q000235:genetics; D013552:Swine
chemical_list: C526472:Smn1 protein, mouse; D055533:Survival of Motor Neuron 1 Protein