Coaxing a Stand-In

by Margaret Wahl on March 1, 2005 - 4:45pm

Bernard Jasmin, Ph.D.

Affiliation:
University of Ottawa, Canada
Strategy:
Utrophin upregulation
Status:
Animal models
 

"The beauty of a drug-based therapy is that you can affect all the muscle fibers,” says Bernard Jasmin, a professor in the Department of Cellular and Molecular Medicine at the University of Ottawa who’s been working on that type of strategy for Duchenne MD.

“Ideally,” he notes, “somebody takes a pill, and it stimulates expression of [a protein] in all the muscles, which right now is a major hurdle for gene delivery.”

Jasmin says he got into studying muscles and nerves because he was “very much into sports” but not very good at them. He didn’t want to be a physician because his mind wanders and he doesn’t like sticking to a schedule. So, in 1985, Jasmin began doctoral studies in biology at the University of Montreal, concentrating on the biochemistry and physiology of muscles and nerves.

Later, doing postdoctoral research at the Pasteur and Jacques Monod Institutes in Paris, he focused on the neuromuscular junction, the place where a fiber from a nerve cell meets a specialized area of a muscle fiber. That focus led him, not surprisingly, to the emerging study of proteins unique to the junction. One of those proteins, identified in the late 1980s, closely resembled the newly discovered dystrophin, the muscle protein missing in DMD.

Originally dubbed dystrophin-related protein and later renamed utrophin, it was found to come from a gene on chromosome 6. Dystrophin is made from a gene on the X chromosome, so it could be assumed that boys with DMD would have intact utrophin genes.

(Jasmin is quick to point out that, although he had speculated about utrophin’s existence, he had little to do with actually identifying it. The credit for that, he says, goes to Kay Davies at the University of Oxford, Lou Kunkel at Harvard, and Tejvir Khurana, now at the University of Pennsylvania.)

Although utrophin is close to dystrophin in both structure and function, there’s at least one key difference between the two proteins. During fetal development and perhaps a little beyond, utrophin is present all around the muscle fiber, interacting with clusters of proteins stuck in its surrounding membrane. As the animal or person matures, utrophin is replaced almost entirely by dystrophin, with one exception. At the neuromuscular junction, utrophin remains throughout life.

Worker in a lab.

By the mid-1990s, investigators were asking a lot of questions. Could utrophin stand in for dystrophin? Is there a mechanism that shuts off utrophin everywhere except the junction as an organism develops? And, if so, could it be disabled, allowing utrophin to resume the position that it has during fetal life?

Protein pathways

Jasmin’s and other groups set out to identify specific pathways that underlie the utrophin-to-dystrophin switch and to make these targets for drug discovery.

Jasmin says his goal is to identify molecules that can trigger or enhance the stimulation of pathways to put utrophin all around the muscle fiber, and “to try to have them specific enough so that you’re not going to have side effects that will do something else. This is where the challenge is.”

Early last year, his group showed that when dystrophin-deficient mice were bred with mice producing higher than normal amounts of the protein calcineurin, the utrophin protein appeared all around the fiber, where dystrophin would have been placed, and it reduced fiber damage.

It may be easier to inhibit something that’s putting a brake on utrophin than to directly increase (upregulate) production of the protein, Jasmin notes. And calcineurin, it turns out, is just the kind of brake release Jasmin and colleagues have in mind.

The brake itself, it seems, is another protein, JNK1. Once the JNK1 brake is overcome by calcineurin, more utrophin can be made, and it extends to areas outside the neuromuscular junction.

In December, Jasmin and colleagues, including MDA grantee Lynn Megeney at the University of Ottawa, showed that corticosteroids like prednisone and deflazacort increase calcineurin activity, which in turn stimulates utrophin production, and that this is likely to be at least part of the reason for their beneficial effects in Duchenne dystrophy.

“We did the proof of principle in the mdx [dystrophin-deficient] mouse, showing that if you stimulate the calcineurin pathway, the mice will be better; and now we find an explanation for the beneficial effect of a drug that is actually used in the clinic. So the whole story is pretty tight as far as we’re concerned.”

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