Scientists at UCLA have identified a new compound that could treat certain types of genetic disorders in muscles. It is a big first step in what they hope will lead to human clinical trials for Duchenne muscular dystrophy (DMD).
DMD is a degenerative muscle disease that affects boys almost exclusively. It involves the progressive degeneration of voluntary and cardiac muscles, severely limiting the life span of sufferers.
In a new study, Carmen Bertoni, Ph.D., assistant professor of neurology, Refik Kayali, Ph.D., a postgraduate fellow in Dr. Bertoni's lab, and their colleagues demonstrate the efficacy of a compound known as RTC13, which suppresses so-called "nonsense" mutations in a mouse model of DMD.
Muscle isolated from a mouse model for DMD that received RT C13 shows protein dystrophin.
Nonsense mutations are generally caused by a single change in DNA, which disrupts the normal cascade of events that changes a gene into messenger RNA, then into a protein. The result is a non-functioning protein. In the case of DMD, the "missing" protein is called dystrophin.
Drs. Bertoni and Kayali collaborated with the laboratory of Richard Gatti, M.D., professor of pathology and laboratory medicine and of human genetics. Working with the UCLA Molecular Shared Screening Resource facility at the campus's California NanoSystems Institute, the Gatti lab screened some 35,000 small molecules in the search for new compounds that could ignore nonsense mutations. Two were identified as promising candidates: RTC13 and RTC14.
Dr. Bertoni's lab tested RTC13 and RTC14 in a mouse model of DMD. While RTC14 was not effective, RTC13 was able to restore significant amounts of dystrophin protein, making the compound a promising drug candidate for DMD. When RTC13 was administered to mice for five weeks, the investigators found that the compound partially restored full-length dystrophin, which resulted in a significant improvement in muscle strength. The loss of muscle strength is a hallmark of DMD.
The next step in the research is to test if an oral formulation of the compound would be effective in achieving therapeutically relevant amounts of dystrophin protein. If so, planning can then begin for clinical testing in patients and for expanding these studies to other diseases that may benefit from this new drug.