BETHESDA, Md.—Duchenne muscular dystrophy (DMD) is caused by a faulty gene that leads to progressive muscle weakness. The degenerative muscle disease usually begins in childhood and has no known cure, and death often occurs around age 25. DMD primarily affects men, with an estimated incidence of one in 3,300 male births, and while women are usually asymptomatic, a small percentage of female carriers manifest milder forms of the disease (symptomatic form of muscular dystrophy of Duchenne and Becker in female carriers).
People with DMD lack dystrophin, a protein similar to a molecular shock-absorber that helps to 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.
Researchers at the National Institutes of Health’s National Center for Advancing Translational Sciences (NCATS) and the University of Nevada, Reno School of Medicine (UNR Med) have demonstrated that a drug originally intended to treat cancer could potentially treat DMD. NCATS conducts and supports research on the science and operation of translation—the process by which interventions to improve health are developed and implemented—to allow more treatments to get to more patients more quickly. The candidate drug, SU9516, represents a different kind of approach. Rather than trying to fix or replace the broken gene, SU9516 accelerates the muscle repair process, helping to reinforce muscle structure.
To find ways to therapeutically target this molecule, the researchers tested a large library of more than 350,000 compounds with proven pharmacological activities that could potentially increase the levels of α7β1 integrin. Among the tested candidates, they identified SU9516, a compound previously developed to target leukemia cells.
“Our findings open the door to develop new drug treatments for DMD,” said NCATS Chemical Genomics Center Acting Branch Chief Dr. Juan Marugan, who led the team along with Dr. Dean Burkin, a UNR Med professor of pharmacology.
Their research showed that SU9516, which had been previously developed as a treatment for leukemia, improved muscle function in both laboratory and animal DMD models. The results, published recently in Molecular Therapy (“SU9516 Increases α7β1 Integrin and Ameliorates Disease Progression in the mdx Mouse Model of Duchenne Muscular Dystrophy”), may provide a promising approach against the disorder and other muscle-wasting conditions.
Burkin, senior author of the current study, and his co-workers showed in a previous study that boosting the levels of a cell structural protein, α7β1 integrin, in affected muscle cells could improve DMD symptoms in a mouse model. Increased amounts of the protein slowed the disease’s progress. The UNR team collaborated with NCATS researchers, including co-team leaders Drs. Marc Ferrer and Noel Southall, to screen a large collection of compounds for molecules that could increase α7β1 integrin production in mouse muscle cells grown in the laboratory. They found 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 preclinical experiments, the researchers demonstrated that SU9516 increased the production of α7β1 integrin in human and mouse DMD muscle cells. Later tests determined that SU9516 also improved muscle function and slowed indicators of disease progression.
According to Burkin, “Integrin stabilizes muscle structure and helps stimulate muscle repair and regeneration. If we can artificially increase its production with drugs, we think it can help protect muscle cells from damage.”
Ferrer of NCATS said that the research began in 2013. The team screened compounds, identified SU9516 and performed assays in animal models. As he explained, “The molecule has a lot of toxic anticancer components that have to be removed, but now we know the real target. It’s a work in progress.”
The team plans to work with medicinal chemists to make the molecule more specific for DMD, while also removing the toxic anticancer components, creating a safer version with a goal of future testing in patients. The work was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) grants R01AR053697, R01AR064338 and R41AR067014, Cure CMD and Struggle Against Muscular Dystrophy.