Duchenne Muscular Dystrophy (DMD) is an inherited disorder caused by mutations in the dystrophin gene. For many years gene therapy has been considered a potential way to cure inherited diseases such as DMD. Despite the effort to make gene therapy safer and more applicable, the host immune response to the vector and the therapeutic gene product is still considered a major barrier to successful gene transfer. We hypothesize that manipulating the immune system of dystrophic mice to recognize dystrophin as a self- component before gene transfer will lead to successful delivery and long-term expression of dystrophin in muscles of these mice. We propose to expand Tregs in the presence of dystrophin protein and to adoptively transfer them into vector-recipient mice to induce dystrophin-specific tolerance in these mice. Results will be obtained from parallel studies to investigate the difference between treating dystrophic mice with high- capacity adenoviral (HC-Ad) and adeno-associated viral (AAV) vectors. These studies will enhance our understanding of effects of inducing antigen-specific tolerance on gene delivery and will ultimately facilitate successful delivery of the dystrophin gene to DMD patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31NS056780-03
Application #
7810630
Study Section
Special Emphasis Panel (ZRG1-F01-P (20))
Program Officer
Porter, John D
Project Start
2008-06-01
Project End
2011-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
3
Fiscal Year
2010
Total Cost
$29,238
Indirect Cost
Name
University of Pittsburgh
Department
Neurology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Eghtesad, Saman; Jhunjhunwala, Siddharth; Little, Steven R et al. (2011) Rapamycin ameliorates dystrophic phenotype in mdx mouse skeletal muscle. Mol Med 17:917-24
Wang, Lei; Eghtesad, Saman; Clemens, Paula R (2011) Migration of dendritic cells from murine skeletal muscle. Immunobiology 216:195-9
Eghtesad, S; Zheng, H; Nakai, H et al. (2010) Effects of irradiating adult mdx mice before full-length dystrophin cDNA transfer on host anti-dystrophin immunity. Gene Ther 17:1181-90
Eghtesad, Saman; Morel, Penelope A; Clemens, Paula R (2009) The companions: regulatory T cells and gene therapy. Immunology 127:1-7