Evaluation of MMX1902 as an Oral Treatment for Duchenne Muscular Dystrophy
Abstract
Objectives/Rationale: Duchenne Muscular Dystrophy (DMD) is one of the most common and devastating genetic diseases of childhood, affecting approximately 1 in 3,500 live male births. The disease often appears between the ages of 2 and 6, leading to walking problems by age 11, loss of upper arm use in the teen years, and heart and respiratory failure leading to death in the early 20s. DMD is a severe, progressive disease resulting from a loss of functional dystrophin protein, which has a structural role in muscle cells and plays a prominent role in cell signaling and regulation of muscle response to stress. Muscle degeneration and inflammatory response, caused by the lack of dystrophin, produce a cellular environment in which adipocytes and fibroblasts proliferate and impair the healing capacity of muscle precursor cells. Skeletal muscle is replaced by fibrosis, and the persistent breakdown of muscle cells compromises the stem cells ability to direct muscle regeneration, resulting in progressive muscle weakness and ultimately death of the patient. Angiotensin 1-7 (A(1-7)) treatment has been shown to mitigate muscle weakness and fibrosis of the diaphragm and large muscles in animal models of DMD. Although A(1-7) administration has also yielded encouraging results in murine models of muscular dystrophy, limitations curb the therapeutic utility as treatments developed with A(1-7) would require multiple daily injections, placing a difficult therapeutic burden on the patient. In order to circumvent these limitations, our laboratory has developed an orally available, novel compound, MMX1902, which mimics the effect of A(1-7). MMX1902 has been found to have comparable, or superior, in vitro and in vivo activities to A(1-7). In a pilot study, MMX1902 delivered via subcutaneous administration reduced muscle inflammation and fibrosis as well as increased muscle strength. We hypothesize that oral administration of MMX1902 will retain the anti-inflammatory and strength increasing properties observed with subcutaneous dosing and induce recovery and regeneration of injured muscles. The overall goals of this proposal are to optimize the oral dosing regimen, evaluate the efficacy of orally administered MMX1902, conduct small-scale GMP (Good Manufacturing Practices) manufacture of MMX1902, and conduct a pre-IND (Investigational New Drug) meeting with the Food and Drug Administration (FDA) in preparation for clinical investigation. Impact: DMD is a severe medical condition that has no cure or efficacious treatment option that can arrest or reverse disease progression. The severity of this condition is exemplified in the cost of disease treatment, which stands at $362-$488 million annually in the United States alone. Current treatments include assisted ventilation, corticosteroid administration, the use of orthopedic devices to support locomotion and prevent contractures, physiotherapy, dietary changes, and corrective surgery; however, since none of these treatments have proven capable of arresting or reversing the progression of the disease, new therapies are desperately needed. Our initial preclinical study results demonstrated an improvement in disease state following subcutaneous treatment with MMX1902 in a murine model of DMD. Results suggest that MMX1902 treatment has the potential to delay disease progression, reverse disease condition, and ultimately prolong the life of individuals suffering from this terminal disease. Successful development of MMX1902 would reduce overall medical costs and improve the treatment, quality of life, and long-term outlook for individuals affected by DMD. Timeline: This proposal supports program progression through completion of a pre-IND meeting with the FDA and will facilitate rapid transition from preclinical evaluation to clinical investigation. If the preclinical results are translated to benefit in the human condition, it is expected that patients may see a treatment benefit
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510455
Entities
People
- Kathleen Rodgers
Organizations
- United States Army
- University of Southern California