Duchenne muscular dystrophy (DMD), which affects approximately 10,000 patients in the United States and 40,000 worldwide, is a rare genetic disorder affecting one in every 3,500 live male births. Mutations in the dystrophin gene result in loss of the dystrophin protein, which causes deterioration of muscle cells. Patients are confined to wheelchairs by age 12 and can die by age 30 due to cardio-respiratory failure. Sarepta Therapeutics has developed an injectable drug that allows the DNA-RNA machinery to effectively “skip over” the mutated portion of the dystrophin gene so that the body can produce functional dystrophin protein. The purpose of this project is to develop this technology into a potential disease-modifying, lifesaving therapy. The technology being developed for this DMD project may be applicable to many other rare genetic disorders, amplifying the project’s impact.
DMD results from mutations in the dystrophin gene that disrupt the mRNA translational reading frame, preventing production of dystrophin, an essential protein that maintains the integrity of muscle cell membranes. Absence of dystrophin leads to severe muscle wasting and affected individuals may succumb to cardio-respiratory failure.
This project exploits the mechanism of exon skipping in which a phosphorodiamidate morpholino oligomer (PMO) binds to dystrophin pre-mRNA such that the targeted exon is skipped in the spliced mRNA. This process bypasses the mutation and restores translation of internally truncated but partially functional dystrophin protein. In recent clinical trials, intravenous injections of the Sarepta Therapeutics PMO-based drug AVI-4658 resulted in production of dystrophin in muscles of treated patients.
In this project, another PMO drug candidate targeting a different mutation within the dystrophin gene will be tested for safety in a series of preclinical studies mandated by the Food and Drug Administration (FDA). If the compound is found to be safe, clinical trials will commence. Successful conclusion of all trials would result in an exon-skipping drug that benefits a separate group of DMD patients from those targeted by AVI-4658. Together, the two compounds would suggest that other compounds of this class may also be safe, facilitating development of PMO-based drugs for additional DMD mutations and expanding the number of patients benefiting from the treatment.
Sarepta Therapeutics, Inc., Bothell, Washington
Peter Sazani, Ph.D.
Public Health Impact
Currently, there is no disease-modifying treatment for DMD, a disease that invariably kills patients before they reach 30 years of age. Existing treatments are palliative and do not change the course of disease. Exon-skipping PMOs, if successful in the clinic, can bring potential lifesaving medications to various DMD patient subpopulations.
The project team performed preclinical efficacy studies to select the candidate molecule for development. After TRND confirmed the lead molecule, Sarepta reclaimed full control of the project, utilizing internal corporate resources to continue development. This TRND project is complete.