Published October 16, 2018
Researchers in the Department of Physiology and Biophysics have developed a promising therapy for Duchenne muscular dystrophy (DMD) that is moving closer to use in humans.
The research by Frederick Sachs, PhD, SUNY Distinguished Professor, and Thomas M. Suchyna, PhD, research assistant professor, demonstrates that the novel drug significantly reduced loss of muscle mass and susceptibility to muscle damage from repeated stimulation in an advanced animal model of DMD.
The report was published in July in Neuromuscular Disorders.
DMD, which occurs only in boys, results from a genetic defect in the structural protein dystrophin, which provides mechanical support to cell membranes. That loss of support transfers stress to mechanosensitive ion channels, causing an abnormal influx of calcium leading to atrophy.
Boys with DMD show signs of physical impairment as young as 3 years old. They are often wheelchair-bound by adolescence and most die by their 20s or 30s, many of cardiac or respiratory failure.
The novel therapy is based on studies of the peptide GsMTx4 or AT-300, the first drug that selectively inhibits mechanosensitive ion channels without disturbing the neuromuscular system.
“GsMTx4 represents an ‘out-of-the-box’ therapy to slow disease progression in DMD,” says Sachs, co-author of the study.
Suchyna, corresponding author on the study, noted that they showed in a previous study that in addition to protecting skeletal muscle, GsMTx4 is protective against cardiomyopathy, a common cause of mortality in DMD patients.
The peptide was originally found in tarantula venom.
GsMTx4 was licensed by UB to the Buffalo-based biotech firm Tonus Therapeutics, which then sublicensed it to Akashi Therapeutics for further development. (Tonus Therapeutics was co-founded by Sachs and both he and Suchyna are officers in the company.)
It is on track for Phase I/II studies in humans in 2020. Now made by chemical synthesis, GsMTx4 is an “orphan drug,” a designation that the U.S. Food and Drug Administration (FDA) awards to promising therapies for rare diseases.
“Remarkably, we saw no side effects in the mice in the current study, nor in ferrets in a previous study on cardiac disease, despite the fact that mechanosensitive piezo channels — the drug’s target — are ubiquitous in living organisms,” Sachs says. The drug also has a long half-life, so that subcutaneous injection may be needed only once a week.
Detailed toxicity testing for an investigatory new drug application to the FDA is planned for spring 2019.
The researchers conclude that GsMTx4 may also complement other therapies, such as anti-inflammatory agents and gene replacement strategies that are being prescribed or studied in DMD.
Other co-authors are Christopher W. Ward, PhD, of the University of Maryland School of Medicine and Ernest D. Bush, PhD, of Akashi Therapeutics.
Funding for the development of this drug came from the Children’s Guild Foundation of Buffalo, the John R. Oishei Foundation, the UB Center for Advanced Technology in Big Data and Health Sciences (UB CAT) and the National Institutes of Health.