MDA grant speeds research toward better treatments for Duchenne muscular dystrophy

| Written by Jessica Moore
Alessandra Dall'Agnese, Lorenzo Puri, M.D., Ph.D., and Sonia Albini, Ph.D.

Pier Lorenzo Puri, M.D., Ph.D., professor in the Development, Aging, and Regeneration Program, has focused his career on finding treatments to counter the progression of Duchenne muscular dystrophy (DMD). A new grant from the Muscular Dystrophy Association, totaling nearly $300,000 for three years of support, will help his team figure out how to improve on a drug that they helped advance to clinical trials.

DMD, which affects hundreds of thousands of boys and young men worldwide, causes progressive muscle weakness that is usually first apparent as a child learns to walk. All patients eventually rely on a wheelchair by their high school years, and few live past their early 20s.

In DMD, the absence of a structural protein called dystrophin leads to the progressive loss of muscle fibers, as they cannot maintain their integrity following contraction. The damage triggers both repair—generation of new muscle cells—and formation of fibrous deposits, which make the muscle stiff. At first, regeneration keeps pace with the damage so the muscle continues to work, but as time goes on, the balance tips to favor scarring.

Whether the muscle regenerates or becomes fibrotic is determined by specialized cells that reside between muscle fibers, called fibro-adipogenic progenitors. The drugs that were first shown to work by Puri’s lab, histone deacetylase inhibitors (HDACis), encourage the pro-regenerative activity of these cells, while preventing them from forming fibrotic scars and promoting fat infiltration.

One HDACi, called givinostat, is in a small clinical trial in Europe. Of the 19 patients enrolled, almost all are responding with more regeneration and less fibrosis and fat infiltration. The trial is expected to expand worldwide.

“Recently, we’ve found that not all interstitial cells switch to promoting fibrosis at once,” Puri explained. “That means only some of them need to be targeted by the drug. Since we’ve figured out how to distinguish the good ones from the bad ones, we’re going to use the grant funds to look further at what’s going on in each subpopulation and see how the drug affects them.

“This research could lead to new ways to specifically target the interstitial cells that need to be redirected to foster muscle renewal.”

Puri’s recent interview on local TV station KUSI about muscular dystrophy and his research is online here.