title: Efficacy and biodistribution analysis of intracerebroventricular administration of an optimized scAAV9-SMN1 vector in a mouse model of spinal muscular atrophy.
abstract: Spinal muscular atrophy (SMA) is an autosomal recessive disease of variable severity caused by mutations in the SMN1 gene. Deficiency of the ubiquitous SMN function results in spinal cord α-motor neuron degeneration and proximal muscle weakness. Gene replacement therapy with recombinant adeno-associated viral (AAV) vectors showed therapeutic efficacy in several animal models of SMA. Here, we report a study aimed at analyzing the efficacy and biodistribution of a serotype-9, self-complementary AAV vector expressing a codon-optimized human SMN1 coding sequence (coSMN1) under the control of the constitutive phosphoglycerate kinase (PGK) promoter in neonatal SMNΔ7 mice, a severe animal model of the disease. We administered the scAAV9-coSMN1 vector in the intracerebroventricular (ICV) space in a dose-escalating mode, and analyzed survival, vector biodistribution and SMN protein expression in the spinal cord and peripheral tissues. All treated mice showed a significant, dose-dependent rescue of lifespan and growth with a median survival of 346 days. Additional administration of vector by an intravenous route (ICV+IV) did not improve survival, and vector biodistribution analysis 90 days postinjection indicated that diffusion from the cerebrospinal fluid to the periphery was sufficient to rescue the SMA phenotype. These results support the preclinical development of SMN1 gene therapy by CSF vector delivery.
authors.affiliation: INSERM UMR 951, Evry, France; Genethon, Evry, France.
authors.forename: Nicole
authors.initials: N
authors.lastname: Armbruster
authors.affiliation: INSERM UMR 951, Evry, France; Genethon, Evry, France.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Lattanzi
authors.affiliation: INSERM UMR 951, Evry, France; Genethon, Evry, France.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Jeavons
authors.affiliation: Genethon , Evry, France.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Van Wittenberghe
authors.affiliation: Genethon , Evry, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Gjata
authors.affiliation: Center of Research in Myology, INSERM UMRS 974, CNRS FRE 3617, Institut de Myologie, Université Pierre et Marie Curie Paris 6 , Paris, France.
authors.forename: Thibaut
authors.initials: T
authors.lastname: Marais
authors.affiliation: Genethon , Evry, France.
authors.forename: Samia
authors.initials: S
authors.lastname: Martin
authors.affiliation: Genethon , Evry, France.
authors.forename: Alban
authors.initials: A
authors.lastname: Vignaud
authors.affiliation: Center of Research in Myology, INSERM UMRS 974, CNRS FRE 3617, Institut de Myologie, Université Pierre et Marie Curie Paris 6 , Paris, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Voit
authors.affiliation: INSERM UMR 951, Evry, France; Genethon, Evry, France.
authors.forename: Fulvio
authors.initials: F
authors.lastname: Mavilio
authors.affiliation: Center of Research in Myology, INSERM UMRS 974, CNRS FRE 3617, Institut de Myologie, Université Pierre et Marie Curie Paris 6 , Paris, France.
authors.forename: Martine
authors.initials: M
authors.lastname: Barkats
authors.affiliation: INSERM UMR 951, Evry, France; Genethon, Evry, France.
authors.forename: Ana
authors.initials: A
authors.lastname: Buj-Bello