California's Stem Cell Agency

Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy and one of the most common fatal genetic disorders. Approximately one in every 3,500 boys worldwide is affected with DMD. Extrapolating from population based studies, there are over 15,000 people currently living with DMD in the US. DMD is a devastating and incurable muscle-wasting disease caused by genetic mutations in the gene that codes for dystrophin, a protein that plays a key role in muscle cell health. Children are typically weaker than typical by age three, and progressive muscle weakness of the legs, pelvis, arms, neck and other areas result in most patients requiring full-time use of a wheelchair by age 11. Eventually, the disease progresses to complete paralysis and increasing difficulty in breathing due to respiratory muscle dysfunction and heart failure. The condition is terminal, and death usually occurs before the age of 25. While corticosteroids can slow disease progression and supportive care can extend lifespan and improve quality of life, no therapies exist that address the primary defect or dramatically alter the debilitating disease course. The Planning Award funded the organization of the scientific and clinical team to apply for a well-defined CIRM Disease Team Therapy Development Award. The PI and project manager travelled to San Francisco to a CIRM sponsored workshop to gain training and insight in developing a Target Product Profile, to meet with other CIRM disease team grantees and aid in developing the most effective grant application. During that trip, we also met with investigators at the California based CRO, SRI, toured the SRI facilities, and planned for the assembly of the team that would us develop appropriate toxicology package for the proposed drug development. Several face-to-face meetings and conference calls with leaders in Duchenne advocacy, DMD clinic directors and industry partners were orchestrated to assess enthusiasm for the proposed project, which was across the board very high. A day long planning grant meeting was held on Dec 9th, 2011 in Santa Monica with participation of over 30 national and local academic, CRO, and industry experts in exon skipping, Duchenne Muscular Dystrophy, clinical trials planning, FDA regulatory practices and drug development. We identified and secured a leading industry partner necessary for streamlining the proposed work. Following the meeting, a series of weekly/daily conference calls between team members from UCLA, SRI and the industry partner enabled us to develop details of the proposal. During the planning grant period we were awarded a provisional patent for the combination therapeutic that is being moved forward in this proposal. Through discussions with leaders in the clinical care of Duchenne Muscular Dystrophy, leaders in antisense mediated exon skipping, and leaders in pre-IND drug development, we built a strong team to propose all IND enabling work to bring a proposed combination therapy for exon skipping as a novel Duchenne muscular dystrophy therapy. Exon-skipping is a promising therapy that aims to repair the expression of the dystrophin protein by altering the RNA, but it is unclear whether it will be effective enough to lead to clinical improvements. We have identified a combination therapy that improves the effectiveness of exon-skipping therapy in mouse muscle and in human DMD patient stem cell derived muscle cells in culture. Because the genetic defect is being directly repaired inside of each muscle cell, this therapy is predicted to lessen the disease severity. The early research and further development of the proposed combination therapy require screening for drug efficacy and toxicity using human DMD patient stem cells including: reprogrammed patient fibroblasts converted into muscle-like cells in culture or when transplanted in mice. These cells are necessary because each patient’s mutation in the dystrophin gene is different. In order to know who will or will not benefit from the exon-skipping therapy, individualized cell culture and mouse transplant models from a number of DMD patients must be created to effectively characterize the combination therapy. The proposed research program will complete necessary efficacy and toxicity studies to allow submission of appropriate material to the FDA to allow testing of this novel combined therapeutic in children with DMD. It will also involve a team of clinical trialists who will incorporate findings in planning optimal trial design and ensure clinical trial readiness by the grants end. Since exon-skipping therapy relies on knowing individual patients exact DNA mutation, this is a form of personalized genetic medicine. While the specific combination therapy being developed here will treat up to 13% of DMD patients, the strategy is likely to be generalized to be able to treat up to 70% of DMD patients.