1. Disease Rescue and Increased Lifespan in a Model of Cardiomyopathy and Muscular Dystrophy by Combined AAV Treatments
- Author
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Alberto Auricchio, Giovanni Di Salvo, Stefania Faraso, Carmen Vitiello, Gerardo Nigro, Raffaele Calabrò, Vincenzo Nigro, Luisa Cutillo, Edoardo Nusco, Nicolina Cristina Sorrentino, Vitiello, C, Faraso, S, Sorrentino, Nc, DI SALVO, Giovanni, Nusco, E, Nigro, Gerardo, Cutillo, L, Calabro', Raffaele, Auricchio, A, and Nigro, Vincenzo
- Subjects
Pathology ,Animals ,Cardiomyopathies ,Cricetinae ,DNA, Complementary ,Dependovirus ,Genetic Therapy ,Genetic Vectors ,Humans ,Muscle, Skeletal ,Muscular Dystrophies ,Myocardium ,Sarcoglycans ,Survival Rate ,Transduction, Genetic ,Cardiomyopathy ,lcsh:Medicine ,Complementary ,Muscular dystrophy ,lcsh:Science ,Neurological Disorders/Movement Disorders ,Multidisciplinary ,Ejection fraction ,Skeletal ,Sarcoglycan ,medicine.anatomical_structure ,muscle disease ,Systemic administration ,Muscle ,Cardiovascular Disorders/Myopathies ,Research Article ,medicine.medical_specialty ,BIO14.6 hamster ,Muscle disorder ,adeno-associated viral (AAV) vectors to transduce heart togethe ,Transduction ,Genetic ,Internal medicine ,medicine ,business.industry ,Genetics and Genomics/Gene Therapy ,lcsh:R ,Skeletal muscle ,DNA ,medicine.disease ,Endocrinology ,Heart failure ,lcsh:Q ,business ,cardiomyopathy - Abstract
Background The BIO14.6 hamster is an excellent animal model for inherited cardiomyopathy, because of its lethal and well-documented course, due to a spontaneous deletion of delta-sarcoglycan gene promoter and first exon. The muscle disease is progressive and average lifespan is 11 months, because heart slowly dilates towards heart failure. Methodology/Principal Findings Based on the ability of adeno-associated viral (AAV) vectors to transduce heart together with skeletal muscle following systemic administration, we delivered human delta-sarcoglycan cDNA into male BIO14.6 hamsters by testing different ages of injection, routes of administration and AAV serotypes. Body-wide restoration of delta-SG expression was associated with functional reconstitution of the sarcoglycan complex and with significant lowering of centralized nuclei and fibrosis in skeletal muscle. Motor ability and cardiac functions were completely rescued. However, BIO14.6 hamsters having less than 70% of fibers recovering sarcoglycan developed cardiomyopathy, even if the total rescued protein was normal. When we used serotype 2/8 in combination with serotype 2/1, lifespan was extended up to 22 months with sustained heart function improvement. Conclusions/Significance Our data support multiple systemic administrations of AAV as a general therapeutic strategy for clinical trials in cardiomyopathies and muscle disorders.
- Published
- 2009