A compound already used to treat pneumonia could become a new therapy for an inherited muscular wasting disease, according to researchers at the University of Oregon and the University of Rochester School of Medicine and Dentistry in New York.
The five-member team reports that pentamidine, when tested in genetically altered mice, counters genetic splicing defects in RNA that lead to type 1 myotonic dystrophy -- one of nine types of muscular dystrophy -- also known as DM1 and Steinart's disease.
The compound was among 26 tested in the UO lab of chemist J. Andrew Berglund. Pentamidine carries approval of the U.S. Food and Drug Administration for treating a severe type of pneumonia in people with weakened immune systems, as well as leishmaniasis, sleeping sickness and some yeast infections. However, levels used successfully in the experiments would be toxic in humans, Berglund said.
With modifications, he added, pentamidine could be adapted to reverse RNA splicing defects that drive type 1 myotonic dystrophy. "The fact that a very small library of compounds yielded a molecule capable of reversing the splicing defects associated with DM1 in both cell and mouse DM1 models suggests that a small molecule strategy could lead to a drug for this disease," he said.
The experiments -- done by former UO doctoral student M. Bryan Warf and Catherine M. Matthys, who has since graduated from the UO, and Rochester's postdoctoral researcher Masayuki Nakamori -- identified pentamidine and neomycin B as compounds that worked against abnormal genetic instructions. Pentamidine, however, was found to be the most effective in the mice. Berglund, a member of the UO Institute of Molecular Biology, and Dr. Charles A. Thornton, a neurologist at Rochester, were co-authors of the study.
The research -- supported primarily by grants from the National Institutes of Health and the Muscular Dystrophy Association -- was published in the Nov. 3 issue of the journal Proceedings of the National Academy of Sciences. In a separate commentary in PNAS, Thomas A. Cooper of the Baylor College of Medicine in Houston hailed the findings, noting that the compound is the first to show such promise of reversing splicing defects. Cooper also noted that such a therapeutic approach is attractive because of the potential benefits to multiple organs affected by the disease.