Phenotypic correction of alpha-sarcoglycan deficiency by intra-arterial injection of a muscle-specific serotype 1 rAAV vector.
alpha-Sarcoglycanopathy (limb-girdle muscular dystrophy type 2D, LGMD2D) is a recessive muscular disorder caused by deficiency in alpha-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 alpha-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, alpha-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 alpha-sarcoglycan gene transfer as a therapeutic approach.
Fougerousse
Francoise
F
Généthon, CNRS UMR8115, 1 rue de l'Internationale, Evry, France.
Bartoli
Marc
M
Poupiot
Jérôme
J
Arandel
Ludovic
L
Durand
Muriel
M
Guerchet
Nicolas
N
Gicquel
Evelyne
E
Danos
Olivier
O
Richard
Isabelle
I
D000818:Animals; D002463:Cell Membrane Permeability; D000229:Dependovirus / Q000145:classification / Q000235:genetics*; D016189:Dystrophin / Q000378:metabolism; D015870:Gene Expression; D005786:Gene Expression Regulation; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000235:genetics*; D006984:Hypertrophy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007269:Injections, Intra-Arterial; D007700:Kinetics; D051379:Mice; D009132:Muscles / Q000378:metabolism*; D009928:Organ Specificity; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D049031:Sarcoglycans / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*
D016189:Dystrophin; D049031:Sarcoglycans