Year 3

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, and girls are rarely affected by the disorder. Extrapolating from population based studies there are about 20,000 boys/men 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 normal 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 near 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. Exon-skipping is a promising therapy that aims to repair the expression of the dystrophin protein by altering the RNA. Here we have identified a combination therapy that improves the effectiveness of exon skipping therapy in mouse muscle and in human DMD cells in culture. The early research and further development of the proposed combination therapy required and requires a form of human stem cell: reprogrammed patient fibroblasts converted into muscle-like cells in culture. 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 models from a number of DMD patients must be created to effectively characterize the combination therapy. The completed research program has identified dosing strategies, demonstrated efficacy of combination therapy in long-term treatment in mice with no indication of toxicity. Further, we have demonstrated similar efficacy in the context of human exon 51 skipping in cultured iDRM from multiple patients with different exon 51 skip amenable mutations. 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 in theory 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.