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).
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