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Investigational drug tested for preventing muscle fiber death in muscular dystrophy
Date:3/16/2008

o be flooded by calcium and reorganize, swell and eventually rupture. This triggers cell death in muscle fibers and leads to the progressive muscle weakness, wasting and often early death associated with muscular dystrophy.

Mice lacking the protein delta-sarcoglycan exhibited severe dystrophy and swelling in both skeletal and heart muscle. When Dr. Molkentin and his colleagues deleted the gene encoding cyclophilin D in these mice, the muscle cells returned to near normal and did not show appreciable signs of swelling and cell death. The investigators repeated the experiment with mice lacking a gene encoding laminin alpha2, which causes a more severe dystrophy, swollen skeletal muscle cells and premature death before the mice reach two months of age. In contrast, mice lacking both laminin alpha2 and cyclophilin D showed much healthier muscle cells, increased body weight and walked more. Also, 75 percent of the mice lacking laminin alpha2 and cyclophilin D lived more than three times longer than mice lacking only laminin alpha2.

These findings led the research team to look for pharmacological treatments that also could inhibit cyclophilin D. The drug cyclosporine is a well-documented inhibitor of the protein, but its use is problematic because it also inhibits a protein, calcineurin, crucial to skeletal muscle cell repair after injury and to the development of skeletal muscle cells. The advantage of Debio-025 is that while it inhibits cyclophilin D and blocks cell death in a number of situations, the drug does not suppress the immune system or block calcineurin. The drug is manufactured by DebioPharm S.A. of Lausanne, Switzerland, which provided Debio-025 for use in the study.

The researchers also found their study may have implications beyond skeletal muscle disease as cyclophilin D deletion reduced cardiac dysfunction caused by calcium-overload induced necrosis. This led the team to suggest that mitochondrial-dependent necrosis may also
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Contact: Nick Miller
513-803-6035
Cincinnati Children's Hospital Medical Center
Source:Eurekalert

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