GsMTx4 a Promising ‘Out-of-the-Box’ Therapy for Advanced DMD, Mouse Study Shows

A new investigational therapy called GsMTx4, developed by researchers at the University of Buffalo and based on a molecule found in tarantula venom, is able to prevent the loss of muscle mass and muscle injury in a mouse model of advanced Duchenne muscular dystrophy (DMD).

These findings were published in the study, “GsMTx4-D provides protection to the D2.mdx mouse,” in Neuromuscular Disorders.

DMD, the most common type of muscular dystrophy, is a genetic disease that leads to progressive deterioration of muscle fibers. It is caused by mutations in the DMD gene that provides instructions for the production of a protein called dystrophin. Dystrophin works together with other proteins to strengthen muscle fibers and protect them from injury as muscles contract and relax.

In mouse models of DMD, ion channels in the muscles that respond to mechanical stimulation are over-activated in the absence of dystrophin, causing an abnormal influx of calcium into the tissue, progressively leading to muscle atrophy and DMD progression. Until now, no therapies designed to target these ion channels have been developed.

The new therapy created at the University of Buffalo is based on a peptide (short protein) originally found in tarantula venom, called GsMTx4, that works by inhibiting the activity of these ion channels in the muscles without affecting the communication between nerve cells and muscle cells.

“GsMTx4 represents an ‘out-of-the-box’ therapy to slow disease progression in DMD,” Frederick Sachs, PhD, a professor of physiology and biophysics at the Jacobs School of Medicine and Biomedical Sciences at the University of Buffalo, said in a press release. Sachs is a co-author on the paper along with Thomas Suchyna, PhD, a research assistant professor in the same department.

In a previous study, Sachs and Suchyna had demonstrated that GsMTx4 was able to protect mice from developing cardiomyopathy (heart disease), a frequent cause of death among DMD patients. In this study, they aimed to analyze the short-term effects of GsMTx4 in a mouse model of advanced DMD.

“If successful, this study would serve as a foundation for exploring GsMTx4-D [the compound derived from the peptide GsMTx4] as a chronic therapy for DMD,” the researchers wrote in the study.

Initial analysis revealed the treatment had a long half-life — nearly one week — when administered through an injection under the skin, meaning that, in theory, an injection once a week would be sufficient as a course of treatment.

To assess its effects on muscle mass, muscle injury susceptibility, and DMD progression, the investigators treated animals with injections for six weeks.

These animals showed a significant reduction in the loss of muscle mass and were less prone to muscle injuries after repeated stimulation.

“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 [exist everywhere] in living organisms,” Sachs said.

“We propose GsMTx4-D represents a promising new therapy to slow disease progression and may complement other therapies such as anti-inflammatory agents and gene-replacement strategies,” the researchers wrote.

GsMTx4 has already been licensed to Tonus Therapeutics and sublicensed to Akashi Therapeutics for further development. It is now scheduled for detailed toxicity testing for an investigational new drug application to the U.S. Food and Drug Administration by spring 2019. If successful, GsMTx4 will then move to Phase 1 and Phase 2 human clinical trials by 2020.