RESEARCHERS BLOCK MOLECULAR WASTE DISPOSAL SYSTEM,
SAVE MUSCLE CELLS

TUCSON, Ariz., Sept. 22, 2003 — Blocking a molecular waste disposal system that normally degrades incomplete or abnormally made proteins is a new pathway toward treatment for a common childhood muscular dystrophy, the Muscular Dystrophy Association (MDA) announced today.

MDA grantee Michael Lisanti of Albert Einstein College of Medicine in New York was part of a U.S. and Italian research group that blocked “proteasomes” — molecular garbage disposal units — in the muscle cells of MD-affected mice.

The team published its results in the October issue of the American Journal of Pathology. (An online preview was published today at http://ajp.amjpathol.org.)

“Many strategies to correct muscular dystrophy rely upon replacing muscle proteins,” said Sharon Hesterlee, MDA director of Research Development. “This approach is unique because it attempts instead to save flawed proteins before they’re discarded.”

The researchers blocked the proteasomes with a compound they injected first into a leg muscle and later delivered via a continuous pump into the muscles of mice with Duchenne muscular dystrophy (DMD), the most common childhood form of the disease.

The underlying problem in DMD is any of a large number of genetic mutations in the gene for dystrophin, with different mutations leading to different types of abnormal dystrophin protein molecules. Cellular waste disposal mechanisms are presumed to get rid of abnormally formed dystrophin molecules, even some that might be useful to the muscles.
In DMD, dystrophin is missing from its normal place in the cell membrane. The disease causes progressive muscle weakness and wasting and usually results in death by the 20s or 30s from respiratory or cardiac muscle failure.

With their proteasomes disabled, the DMD-affected mice, which make short forms of dystrophin, benefited from their dystrophin even though it wasn’t normal. The short dystrophin pieces inserted into the cell membrane, probably similarly to the way full-length dystrophin molecules normally do. Other proteins, missing from the membrane in DMD because of dystrophin’s absence, also assembled properly after the anti-proteasome treatment.

The dystrophin and associated proteins restored the structure and function of the cell membranes and the appearance of the muscle tissue under the microscope, the researchers say.

“This is a very exciting development, as it may open the way toward a new drug treatment for Duchenne and Becker muscular dystrophy, as well as for related muscle diseases,” Lisanti commented.

He said his group used a proteasome-blocking compound that’s only approved for laboratory research but that he knows of a similar drug that’s used in cancer treatment.

MDA is the nonprofit health agency dedicated to curing muscular dystrophy, ALS and related diseases by funding worldwide research. The Association also provides comprehensive health care and support services, advocacy and education.