Autologous Myoblast Transfer: A Combination of Myoblast Transplantation and Gene Therapy

Duchenne Muscular Dystrophy (DMD) is an inherited muscle disease that is characterized by a lack of dystrophin expression in the membrane cytoskeleton of muscle fibers. This lack of dystrophin is responsible for muscle fiber necrosis which leads to the muscle atrophy and progressive muscle weakness, characteristic of the DMD pathology. Myoblast transplantation and gene therapy based on viral vectors have been shown to be efficient in the delivery of genes to skeletal muscle but has been hindered by several limitations. Results from our laboratory and others have shown that adenovirus and herpes simplex virus efficiently infect neonatal muscles, however, within a few days of mouse development, the muscle is largely refractory to transduction with both viral vectors. Since myoblasts possess the ability to fuse with immature and mature myofibers, and viral vectors can efficiently transduce myoblasts, the ex vivo technique can be used as an alternative method to achieve viral gene delivery to mature muscle fibers. We have demonstrated that the myoblast-mediated gene transfer may be used to deliver viral vectors (Adenovirus and herpes simplex virus type 1) into mature muscle. In addition, we have shown that the ex vivo approach using mdx myoblasts engineered with adenoviral vectors, which carry the full-length dystrophin gene, is capable of restoring dystrophin to the injected mdx muscle. Our results suggest that the ex vivo approach may be an alternative way of achieving viral gene delivery to mature muscle and may contribute to the elimination of one of the major hurdles facing the application of gene therapy to skeletal muscle.