Two Anti-Fibrosis Drugs Show
Promise in Mice With DMD

Two drugs, losartan and pirfenidone, have shown promise in reducing fibrosis (scar formation) in mice that lack the muscle protein dystrophin and have a disease resembling Duchenne muscular dystrophy (DMD).

Both drugs target the natural body compound transforming growth factor beta (TGF-beta), which interferes with muscle fiber formation and promotes formation of scar tissue (fibrosis) in response to injury, inflammation or disease.

Fibrosis, the result of excess deposition of connective tissue, is a major factor in muscle function impairment in human DMD.

Luc Gosselin, an MDA research grantee at the State University of New York at Buffalo, and colleagues, who published results of their work with pirfenidone in the February issue of Muscle & Nerve, found the drug was somewhat effective in reducing fibrosis in mice treated for four weeks, but they say more testing at higher doses is needed.

Pirfenidone is in development by InterMune of Brisbane, Calif., for the treatment of interstitial pulmonary fibrosis, a condition in which excess collagen interferes with lung function.

In a separate study, Ronald Cohn at Johns Hopkins University in Baltimore and colleagues, who published their findings online Jan. 21 in Nature Medicine, had more success with another antifibrosis drug, losartan, which they tested in dystrophin-deficient, DMD-affected mice for 6 to 9 months.

In the losartan-treated mice, the diaphragm muscles showed less scarring (fibrosis in 18 percent of the tissue, compared to 32 percent in untreated mice). The mice had significantly better front and back leg grip strength than did their untreated counterparts, showed less muscle fatigue when challenged, and had muscle fibers that looked more normal.

Losartan is approved to treat high blood pressure and is marketed as Cozaar by Merck of Whitehouse Station, N.J., under the brand names Cozaar and Hyzaar.

“We’re very excited about the therapeutic potential of losartan for the treatment of people with Duchenne muscular dystrophy,” said Harry Dietz at the University of Maryland School of Medicine in Baltimore, who led the losartan study team.

“First, it targets a process that appears to directly contribute to an important mechanism of disease -- failure of muscle regeneration in response to injury.

“Second, it has proven remarkably effective in restoring and preserving muscle structure and function in a mouse model of Duchenne muscular dystrophy. The effects are substantial and enduring over the long haul in this mouse model.

“Finally, losartan is a safe medication that has been used extensively in the treatment of hypertension in both adults and children for nearly two decades. It has an exceptional tolerance profile.

“Dr. Cohn and I believe that this therapy has the potential to quickly transition to people with Duchenne muscular dystrophy.

“Given that failure of muscle regeneration to keep pace with muscle destruction is common to many forms of muscular dystrophy, we are also excited at the prospect that this treatment will prove relevant to other inherited and acquired myopathic [muscle disease] states.”