Effect of rapamycin on immunity induced by vector-mediated dystrophin expression in mdx skeletal muscle

• Main Authors: Eghtesad, Saman (Author), Jhunjhunwala, Siddharth (Contributor), Little, Steven R. (Author), Clemens, Paula R. (Author)
• Other Authors: Koch Institute for Integrative Cancer Research at MIT (Contributor)
• Format: Article
• Language: English
• Published: Nature Publishing Group, 2014-07-09T13:54:42Z.
• Subjects: Article
• Online Access: Get fulltext

Duchenne muscular dystrophy (DMD) is caused by mutations in the dystrophin gene. Therapeutic gene replacement of a dystrophin cDNA into dystrophic muscle can provide functional dystrophin protein to the tissue. However, vector-mediated gene transfer is limited by anti-vector and anti-transgene host immunity that causes rejection of the therapeutic protein. We hypothesized that rapamycin (RAPA) would diminish immunity due to vector-delivered recombinant dystrophin in the adult mdx mouse model for DMD. To test this hypothesis, we injected limb muscle of mdx mice with RAPA-containing, poly-lactic-co-glycolic acid (PLGA) microparticles prior to dystrophin gene transfer and analyzed treated tissue after 6 weeks. RAPA decreased host immunity against vector-mediated dystrophin protein, as demonstrated by decreased cellular infiltrates and decreased anti-dystrophin antibody production. The interpretation of the effect of RAPA on recombinant dystrophin expression was complex because of an effect of PLGA microparticles.
National Institutes of Health (U.S.) (F31-NS056780-01A2)
National Center for Research Resources (U.S.) (KL2 RR024154)
United States. Army Medical Research and Materiel Command (grant W81XWH-05-1-0334)