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

Authors :
Passini, Marco A.
Bu, Jie
Richards, Amy M.
Treleaven, Christopher M.
Sullivan, Jennifer A.
O'Riordan, Catherine R.
Scaria, Abraham
Kells, Adrian P.
Samaranch, Lluis
San Sebastian, Waldy
Federici, Thais
Fiandaca, Massimo S.
Boulis, Nicholas M.
Bankiewicz, Krystof S.
Shihabuddin, Lamya S.
Cheng, Seng H.
Source :
Human Gene Therapy. Jul2014, Vol. 25 Issue 7, p619-630. 12p.
Publication Year :
2014

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. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
10430342
Volume :
25
Issue :
7
Database :
Academic Search Index
Journal :
Human Gene Therapy
Publication Type :
Academic Journal
Accession number :
97070949
Full Text :
https://doi.org/10.1089/hum.2014.011