Key result
AAV-delivered delta-sarcoglycan extends lifespan up to 22 months and improves cardiac function in cardiomyopathic hamsters.
Why the study?
The BIO14.6 hamster is an established model for inherited cardiomyopathy with progressive muscle disease and limited lifespan, necessitating therapeutic strategies to restore delta-sarcoglycan expression and improve cardiac and skeletal muscle function.
Does systemic administration of AAV vectors delivering human delta-sarcoglycan cDNA improve lifespan and cardiac function in a hamster model of inherited cardiomyopathy?
Does systemic administration of AAV vectors delivering human delta-sarcoglycan cDNA improve lifespan and cardiac function in a hamster model of inherited cardiomyopathy?
Absolute Event Rate: 10.2% vs 46.9%
p-value: p=0.000038
Systemic AAV-mediated gene therapy successfully rescued cardiac and motor function and doubled lifespan in a preclinical model of inherited cardiomyopathy.
Hypothesis-generating for AAV gene therapy in inherited cardiomyopathy; prospective human trials needed before clinical adoption.
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.
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Vitiello et al. (2009) studied Inherited cardiomyopathy and muscular dystrophy (LGMD2F). AAV-mediated human delta-sarcoglycan gene transfer (AAV2/8 and AAV2/1) vs. Untreated BIO14.6 hamsters was evaluated on Percentage of centralized nuclei in skeletal muscle (p=0.000038). Combined systemic administration of AAV2/8 and AAV2/1 vectors delivering human delta-sarcoglycan extended lifespan up to 22 months and significantly improved cardiac and skeletal muscle function in a hamster model of cardiomyopathy.
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