Efficacy and biodistribution analysis of intracerebroventricular administration of an optimized scAAV9-SMN1 vector in a mouse model of spinal muscular atrophy - CNRS - Centre national de la recherche scientifique Accéder directement au contenu
Article Dans Une Revue Molecular Therapy - Methods and Clinical Development Année : 2016

Efficacy and biodistribution analysis of intracerebroventricular administration of an optimized scAAV9-SMN1 vector in a mouse model of spinal muscular atrophy

Nicole Armbruster
  • Fonction : Auteur
Annalisa Lattanzi
  • Fonction : Auteur
Matthieu Jeavons
  • Fonction : Auteur
Bernard Gjata
  • Fonction : Auteur
Samia Martin
  • Fonction : Auteur
  • PersonId : 938057
Alban Vignaud
  • Fonction : Auteur
Thomas Voit
  • Fonction : Auteur
  • PersonId : 901909
Fulvio Mavilio
Ana Buj-Bello

Résumé

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.
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hal-01487810 , version 1 (13-03-2017)

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Nicole Armbruster, Annalisa Lattanzi, Matthieu Jeavons, Laetitia van Wittenberghe, Bernard Gjata, et al.. Efficacy and biodistribution analysis of intracerebroventricular administration of an optimized scAAV9-SMN1 vector in a mouse model of spinal muscular atrophy. Molecular Therapy - Methods and Clinical Development, 2016, 3, pp.UNSP 16060. ⟨10.1038/mtm.2016.60⟩. ⟨hal-01487810⟩
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