EMBARGOED BY PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES FOR 5 pm EDT MONDAY, APRIL 15, 2002

Enzyme Halts Muscle Waste In Mouse Models
Of Most-Common Childhood Muscular Dystrophy

The muscle destruction associated with Duchenne muscular dystrophy (DMD), the most common childhood form of muscular dystrophy, is halted in mice when supplemental amounts of a naturally occurring enzyme are added to the skeletal muscle.

These results from researchers at the University of California, San Diego (UCSD) School of Medicine are published in the April 16, 2002 issue of the journal Proceedings of the National Academy of Sciences.

Muscle wasting associated with DMD was inhibited after the UCSD team added an enzyme called CT GalNAc transferase to skeletal muscles in mice bred to develop DMD. Normally, CT GalNAc transferase is expressed in another area of the muscle, the neuromuscular junction, where nerves send impulses to muscle fiber. The UCSD team was able to re-position the enzyme so that it was available in the DMD-vulnerable skeletal muscle, which is the structural tissue that supports body movement.

Paul Martin, Ph.D. 

"We hope this enzyme can eventually be used as a therapy for Duchenne muscular dystrophy," said Paul Martin, Ph.D., UCSD assistant professor of neurosciences, a member of the UCSD Glycobiology Training and Research Center, and the study's senior author. "It has the potential for managing the disease, much like we manage diabetes with insulin medication or injections."

The disease strikes one in 5,000 children, almost exclusively boys, before they reach the age of 6. DMD frequently leaves its victims wheelchair-bound by age 12 and most DMD children die in their early 20s. The disease is caused by a mutation in a protein called dystrophin, which helps anchor muscle fibers to the connective tissue surrounding them.

"Losing dystrophin is like losing the foundation of your house," Martin said. "Without that foundation, the house falls apart. Without dystrophin, muscles affected by DMD become damaged and break."

Martin discovered the enzyme as he looked for other proteins that might compensate for the disabled dystrophin in DMD patients. Normally, CT GalNAc transferase acts as a chemical stimulant to generate scaffold-like tissue at the neuromuscular junction. In research reported earlier this year in the journal Developmental Biology (242, 58-73), Martin and his team described the role of CT GalNAc transferase and their development of mice (called CT mice) that had the enzyme available in skeletal muscles, as well as the neuromuscular junction. These mice did not develop the DMD muscle wasting.

Holly H. Nguyen and Paul Martin, Ph.D. 

In their most recent experiments, the Martin team bred the CT mice to mice that lacked the dystrophin gene (called mdx mice). While mdx mice developed muscle wasting indicative of DMD, the disease did not develop in the new breed of CT-mdx mice.

The next steps for Martin's lab will be to refine the science behind the use of CT GalNAc transferase for DMD. Although he hesitates to say when a therapy might be available for human clinical trials, Martin notes that it may require a pharmaceutical company that is willing to invest in drug development.

"There are two schools of thought about how to develop a therapy," he said. "One option is gene therapy. Although a small amount of enzyme would have a big effect, the mechanics of administering the gene to all muscles in the body would not be an easy task. We're more excited about the possibility of creating an easy-to-administer oral medication that could globally stimulate this enzyme in skeletal muscles."

In addition to Martin, additional authors of the study were Holly H. Nguyen, a second year UCSD medical student, and UCSD researchers Vianney Jayasinha, Bing Zia, and Kwame Hoyte.

The work was funded by grants from the Multiple Dystrophy Association, the March of Dimes, and the National Institutes of Health.

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spondrom@ucsd.edu

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