Our lab studies the muscular dystrophies, diseases that cause muscle degeneration. Our major focus is the most prevalent and severe muscular dystrophy, Duchenne Muscular Dystrophy. DMD is an X-linked inherited disease that occurs in approximately 1/5000 male births. DMD boys are diagnosed at age 2-3. Their mobility declines to the extent that most are in wheelchairs by age 10-15. Cardiomyopathy becomes a problem in their 20s and most DMD boys die in their late 20s and early 30s. Currently, there is no treatment for this devastating disease.
The cause of DMD is mutations in the dystrophin gene, one of the largest genes in the human genome. Dystrophin is a very large protein (427 kDa) localized on the sarcolemma of skeletal cardiac muscle. For gene therapy, the dystrophin cDNA is far too large to fit into AAV. Current trials are using a micro-dystrophin that encodes only about 20% of the protein. Micro-dystrophins improve the dystrophic phenotype in the mdx mouse model of DMD, but recent clinical trials do not appear to improve muscle function in DMD boys.
We have developed a non-viral platform that targets genes to skeletal and cardiac muscle. Our platform has several important advantages over AAV. Our platform can deliver genes of any size. Also, the genes can be delivered more than once (a major limitation of AAV). Finally, toxicity problems encountered with high doses of AAV required for skeletal muscle are avoided with our platform. Non-viral delivery of full-length dystrophin would be a major step toward treatment of this devastating disease. Our non-viral platform will revolutionize gene therapy in skeletal and cardiac muscle diseases.