GsMTx4-D is a potent protectant of skeletal and cardiac muscle with favorable pharmacokinetics for long-term treatment of muscular dystrophy.


Non-Gene Targeting Therapies

Poster Number: 126


Thomas Suchyna, PhD, Christopher Ward, PhD, Frederick Sachs, PhD, Jinli Wang, PhD, Yina Ma, PhD, Ji Li, PhD


1. SUNY at Buffalo, Jacobs School of Medicine, 2. University of Maryland School of Medicine, 3. SUNY at Buffalo, Jacobs School of Medicine, 4. SUNY at Buffalo, Jacobs School of Medicine, 5. SUNY at Buffalo, Jacobs School of Medicine, 6. SUNY at Buffalo, Jacobs School of Medicine

Duchenne muscular dystrophy is a life-limiting muscle wasting disease that has no current effective therapy. Skeletal muscle degeneration leads to loss of ambulation by the teenage years. However, the most common cause of death is from progressive changes in heart function, typically include arrhythmias, congestive heart failure, and dilated cardiomyopathy, so that new treatments targeting protection of both skeletal and cardiac muscle are desirable. Despite mounting evidence that dysregulation of mechanosensitive ion channels (MSC) is a significant contributor to dystrophy pathogenesis, effective pharmacologic strategies targeting these channels are lacking. GsMTx4-D is a modified peptide inhibitor of MSCs with more favorable pharmacodynamics than its original L-amino acid form. Here we demonstrate, in two separate studies, the muscle protective properties of GsMTx4-D in 1) D2.mdx mice – a more severe dystrophic mouse that more closely models human DMD – treated for 6 weeks with 1 or 10 mg/kg peptide, and 2) in acute treatment of a mouse model of cardiac ischemic reperfusion injury at the same concentrations. GsMTx4-D showed a 1-week half-life when administered by either IV or subcutaneous injection. The D2.mdx mice treated for 6 weeks with GsMTx4-D showed a reduction in the loss of muscle mass and a decrease in susceptibility to contraction induced injury. In the reperfusion injury model, the infarct size was reduced by ~40% in the presence of GsMTx4-D, cardiac output was improved, and arrhythmic events diminished. Importantly, even though all cells in the body contain MSCs, acute treatment of ferrets with similar concentrations of GsMTx4-D had no effect on normal cardiac output or electrical activity, suggesting these receptors are primarily indicators of pathological cell membrane forces. These studies suggest that GsMTx4-D is a promising new strategy for protecting skeletal and cardiac muscle in DMD patients and may be useful as an adjuvant to gene therapies.