title: Use of a lower dosage liver-detargeted AAV vector to prevent hamster muscular dystrophy.
abstract: The BIO14.6 hamster carries a mutation in the delta sarcoglycan gene causing muscular dystrophy and cardiomyopathy. The disease can be prevented by systemic delivery of delta sarcoglycan cDNA using adeno-associated viruses (AAVs). However, all AAVs also target the liver, raising concerns about their therapeutic efficacy in human applications. We compared the AAV2/8 with the chimeric AAV2/2i8, in which the 585-QQNTAP-590 motif of the AAV8 serotype was added to the heparan sulfate receptor footprint of the AAV2 strain. Both vectors carrying the human delta sarcoglycan cDNA were delivered into 24 14-day-old BIO14.6 hamsters. We followed transgene expression in muscle and liver for 7 months. We detected a sustained ectopic expression of delta sarcoglycan in the liver when using AAV2/8 but not AAV2/2i8. Genomic copies of AAV2/2i8 were not detectable in the liver, while at least 100-fold more copies of AAV2/8 were counted. In contrast, the hamster skeletal muscle expressed more delta sarcoglycan using AAV2/2i8 and were still healthy after 7 months at the lower dosage. We conclude that this chimeric vector is a robust option for safer and longer-term diseased muscle targeting.
authors: Telethon Institute of Genetics and Medicine, Via Pietro Castellino 111, 80131 Napoli, Italy.
authors: Ida Luisa
authors: IL
authors: Rotundo
authors: Alessio
authors: A
authors: Lancioni
authors: Marco
authors: M
authors: Savarese
authors: Luca
authors: L
authors: D'Orsi
authors: Michele
authors: M
authors: Iacomino
authors: Gerardo
authors: G
authors: Nigro
authors: Giulio
authors: G
authors: Piluso
authors: Alberto
authors: A
authors: Auricchio
authors: Vincenzo
authors: V
authors: Nigro
mesh_terms: D000818:Animals; D006224:Cricetinae; D018076:DNA, Complementary / Q000235:genetics / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics*; D015316:Genetic Therapy; D005822:Genetic Vectors; D008099:Liver / Q000378:metabolism*; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism; D009136:Muscular Dystrophies / Q000235:genetics / Q000517:prevention & control*; D049031:Sarcoglycans / Q000235:genetics / Q000378:metabolism; D019076:Transgenes
chemical_list: D018076:DNA, Complementary; D049031:Sarcoglycans