Disease Team Therapy Development - Research
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 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 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. 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.
Statement of Benefit to California:
Duchenne muscular dystrophy (DMD) is an incurable and inevitably fatal genetic disorder. It is caused by a defect in the gene that produces dystrophin, a protein critical to the function of normal skeletal muscle. DMD affects more than 1,000 patients in California, 15,000 nationwide, and 300,000 worldwide. Because the genetic mutation responsible for the disease occurs on the X chromosome, the overwhelming majority of patients are male. Children are typically diagnosed when they are toddlers. Muscle weakness first appears in the hips and legs and progressively extends to every muscle in the body, including the arms, neck, diaphragm and heart. By age 11, most patients require full-time use of a wheelchair . By their late teens, they have trouble feeding themselves. Inevitably, patients are completely paralyzed and cannot breathe without a ventilator. As their cardiac muscles fails, they develop heart failure. Patients usually die by age 25. Aside from the human suffering caused by DMD, the disease places a large economic burden on patients, their families and society as a whole. Patients require intensive medical care because they cannot perform the simplest activities of daily living. Eventually, each individual requires ventilation and 24/7 care due to progressive loss of all muscle function. The proposed combination therapy is intended to spare skeletal muscle by producing dystrophin. Specifically, the combination therapy will induce skipping of DMD exon 51 in skeletal muscle; a defect in exon 51 is responsbile for 13% of DMD cases. The therapy causes the dystrophin gene inside each muscle cell to express an internally deleted but partially functional dystrophin protein, lessening the severity of DMD. The approach has been well-validated in animal DMD models. A therapy that effectively slows or reverses disease will allow patients to lead longer, more productive lives and reduce the need for costly supportive services—progress that will benefit patients, their families and society.