Heart failure and muscular dystrophies are two prominent diseases afflicting a large human population worldwide. The long-term goal of this proposal is to develop simple, safe and efficient strategies for gene transfer into both cardiac and skeletal muscles to achieve widespread and sustained transgene expression, which remains a challenging task particularly for systemic vector delivery through blood circulation. The immediate goal is to test the gene delivery and therapeutic strategies in a delta -sarcoglycan (delta -SG) deficient Syrian hamster model, a well-established congestive heart failure and muscular dystrophy animal model. In both humans and animals, a subset of limbgirdle muscular dystrophies (LGMD) caused by mutations in the sarcoglycan genes manifest both cardiomyopathy (CM) and muscular dystrophy. Recent advancement in AAV vectors has equipped us with a promising gene delivery vehicle. Gene therapy may now present a good opportunity for the development of novel therapeutics for LGMD in particular, and cardiomyopathy and muscular dystrophies in general. We have four specific aims in this proposal: 1) to identify the most efficient AAV serotype vectors for blood vessel-mediated cardiac and muscle gene transfer; 2) to study the gene therapy efficacy of congestive heart failure; 3) to study the gene therapy efficacy of sarcoglycan deficiency after intravascular and systemic delivery of the delta -sarcoglycan gene; 4) to improve heart-specific and muscle-specific transduction by a combination of targeted vector delivery and tissue-specific promoters.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
2R01AR045967-06
Application #
6830398
Study Section
Special Emphasis Panel (ZRG1-GTIE (90))
Program Officer
Nuckolls, Glen H
Project Start
1999-04-28
Project End
2009-06-30
Budget Start
2004-09-16
Budget End
2005-06-30
Support Year
6
Fiscal Year
2004
Total Cost
$331,217
Indirect Cost
Name
University of Pittsburgh
Department
Genetics
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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He, Bo; Tang, Ru-hang; Weisleder, Noah et al. (2012) Enhancing muscle membrane repair by gene delivery of MG53 ameliorates muscular dystrophy and heart failure in ?-Sarcoglycan-deficient hamsters. Mol Ther 20:727-35
Qiao, Chunping; Yuan, Zhenhua; Li, Jianbin et al. (2012) Single tyrosine mutation in AAV8 and AAV9 capsids is insufficient to enhance gene delivery to skeletal muscle and heart. Hum Gene Ther Methods 23:29-37
Yang, Lin; Li, Juan; Xiao, Xiao (2011) Directed evolution of adeno-associated virus (AAV) as vector for muscle gene therapy. Methods Mol Biol 709:127-39
Hoshijima, Masahiko; Hayashi, Takeharu; Jeon, Young E et al. (2011) Delta-sarcoglycan gene therapy halts progression of cardiac dysfunction, improves respiratory failure, and prolongs life in myopathic hamsters. Circ Heart Fail 4:89-97
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Qiao, C; Yuan, Z; Li, J et al. (2011) Liver-specific microRNA-122 target sequences incorporated in AAV vectors efficiently inhibits transgene expression in the liver. Gene Ther 18:403-10
Qiao, Chunping; Zhang, Wei; Yuan, Zhenhua et al. (2010) Adeno-associated virus serotype 6 capsid tyrosine-to-phenylalanine mutations improve gene transfer to skeletal muscle. Hum Gene Ther 21:1343-8
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