April 3, 2008

Debio-025 Helps Mice With Two Forms of MD

A compound that protects cellular structures known as mitochondria from damage is beneficial in mice with two forms of muscular dystrophy, investigators have found.

Jeffery Molkentin at Cincinnati Children’s Hospital Medical Center and colleagues, including H. Lee Sweeney at the University of Pennsylvania, who has MDA funding for related work, published their findings online March 16 in Nature Medicine.

First, the investigators analyzed mice with two forms of MD that were also bred not to produce a protein called cyclophilin D.

The lack of cyclophilin D prevented much of the damage that would have been expected in the delta-sarcoglycan-deficient mouse model of type 2F limb-girdle MD (LGMD2F) and the laminin-2-deficient mouse model of congenital MD through its apparent protection of mitochondria, the energy-producing structures inside cells.

In both these forms of MD, as well as in Duchenne MD (DMD), the membrane surrounding each muscle fiber allows excess calcium to flow into muscle cells, which, in part through cyclophilin D’s actions, causes swelling and destruction of mitochondria. Without cyclophilin D, the researchers found, the mitochondria of MD-affected mice demonstrated resistance to this type of damage.

They next tested Debio-025 (made by DebioPharm of Lausanne, Switzerland), a known inhibitor of cyclophilin D, in mice with LGMD2F and mice with DMD, which is caused by a lack of the dystrophin protein.

The mitochondria of these mice were also protected. In addition, the DMD-affected mice treated with Debio-025 from four to 10 weeks of age showed better muscle-fiber organization and less scar tissue than was seen in untreated DMD-affected mice.

Similar effects were seen in LGMD2F-affected mice treated with Debio-025 from age four to age 10 weeks, and these mice also showed better cardiac muscle health than did untreated LGMD2F-affected mice.

The researchers say their results suggest that protecting muscle-fiber mitochondria by inhibiting cyclophilin D could become a new approach for treating muscular dystrophies that are associated with defective muscle-fiber membranes.