AVI-4038 for Treatment of Duchenne Muscular Dystrophy

Duchenne muscular dystrophy (DMD) affects approximately 10,000 patients in the U.S. and 40,000 worldwide. 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 die by age 30 due to cardio-respiratory failure. Sarepta Therapeutics has developed an injectable biologic (oligonucleotide) drug that allows the DNA-RNA machinery to effectively “skip over” the mutated portion of the dystrophin gene, so that functional dystrophin protein can be produced. 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 will be applicable to many other rare genetic disorders, amplifying the impact of this project.

Scientific Synopsis

Duchenne muscular dystrophy (DMD) is a rare and severe genetic disorder affecting one in every 3,500 live male births. There are about 10,000 DMD patients in the United States and 40,000 worldwide. 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 muscle wasting; affected individuals usually require wheelchair before the age of 12 and succumb to cardio-respiratory failure before reaching 30 years of age. 

This project exploits the mechanism of exon skipping by which an oligonucleotide analog 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 AVI Biopharma's drug, AVI-4658, resulted in a mutation specific production of dystrophin in muscles of treated patients. AVI-4658 is a PMO (phosphorodiamidate morpholino oligomer). 

In this project, another PMO drug candidate will be tested for safety in a series of Food and Drug Administration (FDA) mandated pre-clinical studies and, if the compound is found safe, in clinical trials. Successful conclusion of all trials would result in an exon-skipping drug that benefits a separate group of DMD patients. Together, the two compounds would suggest that their safe characteristics are shared by other compounds of this class, facilitating development of drugs for additional DMD mutations and expanding the number of patients benefiting from the treatment.

Key Investigator

Sarepta Therapeutics, Inc., Bothell, Wa.
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 life-saving medications to various DMD patient subpopulations.

Outcomes

The project team currently is performing pre-clinical efficacy studies to select the best candidate molecule for development. Once the lead molecule is selected, TRND support will include manufacturing of the lead molecule in accordance with FDA guidance, as well as the animal toxicology studies necessary to demonstrate safety and support filing an investigational new drug application with the FDA.