The purpose of this Program Project is to focus on the basic research problems that must be solved in order to set the stage for gene therapy for Duchenne muscular dystrophy. Each unit is designed to address one of four areas of necessary basic research. Unit 1 will focus on the development of new adenovirus vectors. The goal will be to create recombinant adenoviruses that have long term expression, do not elict an immune response and that are capable of packaging as large a dystrophin construct as needed. Unit 2 will address the issue of viral d=livery into neonatal and adult mammals. Practical gene therapy will require the development of efficient viral delivery to and uptake by the target tissues. Unit 3 will utilize transgenic mdx mice to examine the effects of dystrophin expression in a variety of target tissues under the control of tissue-specific and non-specific promoters. Additionally Unit 3, in conjunction with Univ 4, will define the amount of protection afforded to muscle by various truncated dystrophin constructs. Unit 4 will focus on the functional protection afforded to the muscles and neuromuscular junctions of mdx mice via the expression of various dystrophic constructs in either transgenic animals (collaboration with Unit 3)) or in recombinant adenovirus-infected animals (collaboration with Units 1 and 2).

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Program Projects (P01)
Project #
5P01AR043648-03
Application #
2442841
Study Section
Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
Project Start
1995-08-10
Project End
2000-06-30
Budget Start
1997-07-01
Budget End
1998-06-30
Support Year
3
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Physiology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Zoltick, P W; Chirmule, N; Schnell, M A et al. (2001) Biology of E1-deleted adenovirus vectors in nonhuman primate muscle. J Virol 75:5222-9
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Croyle, M A; Chirmule, N; Zhang, Y et al. (2001) ""Stealth"" adenoviruses blunt cell-mediated and humoral immune responses against the virus and allow for significant gene expression upon readministration in the lung. J Virol 75:4792-801
Gao, G; Qu, G; Burnham, M S et al. (2000) Purification of recombinant adeno-associated virus vectors by column chromatography and its performance in vivo. Hum Gene Ther 11:2079-91
Chirmule, N; Xiao, W; Truneh, A et al. (2000) Humoral immunity to adeno-associated virus type 2 vectors following administration to murine and nonhuman primate muscle. J Virol 74:2420-5
Cordier, L; Hack, A A; Scott, M O et al. (2000) Rescue of skeletal muscles of gamma-sarcoglycan-deficient mice with adeno-associated virus-mediated gene transfer. Mol Ther 1:119-29

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