Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder that is primarily characterized by the progressive loss of mass and strength. Despite the advancement of gene and molecular therapy for DMD, there is no cure for this disease. Muscles of DMD patients and of the dystrophic mdx mouse model exhibit elevated numbers of immune cells, primarily macrophages. A growing body of research demonstrates that the immune response to dystrophic muscle modulates muscle injury and regeneration. In chronic injuries, like muscular dystrophy, these interactions can become disrupted and exacerbate the pathology. The ability of macrophages to migrate to sites of muscle injury and modulate injury and repair makes these cells ideal vehicles to deliver therapeutic molecules to injured muscle, as needed. The main goal of this investigation is to genetically modify the hematopoietic stem cells (HSCs), from which macrophages are derived, so that upon transplantation the modified macrophages will express therapeutic molecules that can ameliorate the DMD pathology. Our strategy is to precondition dystrophic mdx mice with non-myeloablative drug busulfan, then transplant HSCs that have been genetically modified ex vivo to express a therapeutic gene, and then assay for the effects on muscle function and the pathology. The results from this study will provide a new platform for delivering therapeutic molecules to DMD muscle in a site-specific manner. This new therapeutic strategy can also be expanded to other forms of muscular dystrophies as well as other diseases where the inflammation and immune cells mediate the pathology.
Duchenne muscular dystrophy (DMD) is an inherited X-linked disorder that is primarily characterized by the progressive loss of mass and strength. Dystrophic muscle also experiences substantial inflammation, in which immune cells can disrupt normal muscle repair and regeneration and accelerate pathology. In this investigation, we will develop a novel therapeutic approach in which immune cells are genetically modified to become vehicles for targeted delivery of therapeutic molecules to dystrophic muscle and ameliorate the DMD pathology.