Phenotypic Correction of |[alpha]|-Sarcoglycan Deficiency by Intra-arterial Injection of a Muscle-specific Serotype 1 rAAV Vector

doi:doi:10.1038/sj.mt.6300022

Subject Categories: Monogenic Disease

Molecular Therapy (2007) 15, 53–61. doi:10.1038/sj.mt.6300022

Phenotypic Correction of -Sarcoglycan Deficiency by Intra-arterial Injection of a Muscle-specific Serotype 1 rAAV Vector

Francoise Fougerousse^1,2, Marc Bartoli^1,2, Jérôme Poupiot¹, Ludovic Arandel¹, Muriel Durand¹, Nicolas Guerchet¹, Evelyne Gicquel¹, Olivier Danos¹ and Isabelle Richard¹

¹Généthon, CNRS UMR8115, 1 rue de l'Internationale, Evry, France

Correspondence: Isabelle Richard, Généthon – CNRS UMR8115, 1 rue de l'internationale, 91000 Evry, France. E-mail: richard@genethon.fr

²These authors contributed equally to this work.

Received 29 June 2006; Accepted 14 September 2006.

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Abstract

-Sarcoglycanopathy (limb-girdle muscular dystrophy type 2D, LGMD2D) is a recessive muscular disorder caused by deficiency in -sarcoglycan, a transmembrane protein part of the dystrophin-associated complex. To date, no treatment exists for this disease. We constructed recombinant pseudotype-1 adeno-associated virus (rAAV) vectors expressing the human -sarcoglycan cDNA from a ubiquitous or a muscle-specific promoter. Evidence of specific immune response leading to disappearance of the vector was observed with the ubiquitous promoter. In contrast, efficient and sustained transgene expression with correct sarcolemmal localization and without evident toxicity was obtained with the muscle-specific promoter after intra-arterial injection into the limbs of an LGMD2D murine model. Transgene expression resulted in restoration of the sarcoglycan complex, histological improvement, membrane stabilization, and correction of pseudohypertrophy. More importantly, -sarcoglycan transfer produced full rescue of the contractile force deficits and stretch sensibility and led to an increase of the global activity of the animals when both posterior limbs are injected. Our results establish the feasibility for AAV-mediated -sarcoglycan gene transfer as a therapeutic approach.