Researchers at the National Institutes of Health’s National Center for Advancing Translational Sciences (NCATS) and at the University of Nevada Reno School of Medicine (UNR Med) have demonstrated that a drug originally targeted unsuccessfully to treat cancer may have new life as a potential treatment for patients with Duchenne muscular dystrophy (DMD).
The candidate drug, SU9516, represents a different approach to treating DMD, a degenerative muscle disease that usually begins in childhood and has no known cure. It is caused by a faulty gene that leads to progressive muscle weakness, with death often occurring around age 25. Rather than trying to fix or replace the broken gene, SU9516 ramps up the muscle repair process, helping reinforce muscle structure.
The team screened more than 350,000 compounds to find SU9516, which had been previously developed as a treatment for leukemia. The research demonstrated that this compound improved muscle function in both laboratory and animal models of DMD. The results, published in Molecular Therapy, may provide a promising approach against the disorder and other muscle-wasting conditions, according to the authors.
Individuals with DMD lack dystrophin, a protein akin to a molecular shock-absorber that helps keep muscle cells intact. Without dystrophin, muscles are fragile and easily injured. Individuals lose muscle strength and the ability to repair damaged muscle tissue. Most die from heart or respiratory problems.
In earlier research, Dean Burkin, PhD, a professor of pharmacology at UNR Med, who was senior author of the current study, and his colleagues showed that boosting the levels of a cell structural protein, α7β1 integrin, in affected muscle cells could alleviate DMD symptoms in a mouse model. In addition, increased amounts of the protein slowed the disease’s progress.
Burkin and his colleagues collaborated with NCATS researchers to screen a large collection of compounds for molecules that could increase α7β1 integrin production in mouse muscle cells grown in the laboratory. The screen revealed that SU9516 raised integrin production and promoted the formation of muscle cells and fibers from DMD muscle stem cells, another important indication of its potential as a drug.
In a series of preclinical experiments, the researchers showed that SU9516 increased the production of α7β1 integrin in human and mouse DMD muscle cells. Subsequent tests found that SU9516 improved muscle function and slowed indicators of disease progression.
Burkin suggests that such a drug could be used alone or in combination with other therapies yet to be developed. There might be wide-ranging applications to other muscle-damaging conditions, such as cachexia, and the effects of aging and injury, he noted.
“Integrin stabilizes muscle structure and helps stimulate muscle repair and regeneration,” Burkin said. “If we can artificially increase its production with drugs, we think it can help protect muscle cells from damage.”
The NCATS–UNR Med team plans to work with medicinal chemists to make the molecule more specific for DMD while removing the toxic anticancer components, thereby creating a safer version, with the goal of future testing in patients with DMD.
Source: NIH; June 13, 2017.