Principal Investigator: Paula Clemens
Abstract: DESCRIPTION (Abstract): Therapeutic gene transfer is a logical approach to the treatment of inherited genetic deficiency diseases, many of which have no other adequate treatment. However, persistent expression of the therapeutic gene in the target tissue and/or the capability of repeat administration will be required. To date, adenoviral (Ad) vector- mediated gene transfer trials have resulted in an immune response that eliminates the therapeutic protein. This immunity may be due either to the expression of the therapeutic protein itself, to Ad proteins or both. The future success of human gene therapy trials using the Ad vector as a vehicle will likely depend on a comprehensive understanding of this immune response and novel strategies to modulate it. Although the therapeutic protein to be provided by a gene therapy vector is a self-protein in healthy individuals, the patients who would be treated by gene transfer lack this self-protein due to a germ-line mutation (a null mutant). Examples include Factor IX deficiency, cystic fibrosis and Duchenne's muscular dystrophy (DMD). DMD provides an excellent model with which to study gene transfer treatment for an inherited protein deficiency because the mutant gene and defective protein are known, the target tissue is easily accessible and the mdx mouse strain, which models human DMD, is readily available. The investigators recently have described the development and use of a novel high-capacity Ad vector that has all viral genes removed and can accommodate 30 kb of insert DNA. This vector is the most promising to date for decreasing the immunity induced by therapeutic Ad vector- mediated gene delivery; no AD antigens are expressed from the vector, and the use of a muscle-specific promoter should reduce antigen presentation by professional antigen presenting cells. The five aims of this application will lead to the characterization and modulation of the immune response induced by therapeutic gene delivery to skeletal muscle. The first group (Aims 1, 2 and 3) will analyze the immune response to specific antigens. The second group (Aims 4 and 5) has as a common thread the modification of vector characteristics to improve high- capacity Ad vector-mediated gene delivery to muscle by modulating the immune response to the antigens studies in Aims 1-3.
Funding Period: 1999-01-01 - 2005-12-31
more information: NIH RePORT