Research Updates September-October 2005

Article Highlights:

Update on research, clinical trials and studies as of August 2005

by Quest Staff on September 1, 2005 - 3:09pm

QUEST Vol. 12, No. 5

In this article, the latest research news about: New Wellstone Center * Consortium to develop exon-skipping DMD treatment * Respiratory training helps mice with Duchenne MD * Grantees honored

University of Iowa named Wellstone Center

In July, the National Institutes of Health named the University of Iowa in Iowa City the fourth Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center.

Kevin Campbell
Kevin Campbell

The establishment of these centers results from the passage of the MDA-backed MD-CARE Act in 2001. The first three, which are co-funded by NIH and MDA, are located at the University of Washington in Seattle, the University of Rochester (N.Y.), and the University of Pittsburgh.

The lead investigator at the Iowa Wellstone Center is muscle physiologist Kevin Campbell, a longtime MDA research grantee.

The center's projects will explore basic biological mechanisms that relate to possible treatments for muscular dystrophies, encourage the translation of research from lab to clinic and provide advanced diagnostic services.

Campbell will lead an investigation of whether improving muscle cell membrane maintenance, particularly through increasing levels of proteins known as LARGE and dysferlin, can provide a basis for new Duchenne muscular dystrophy treatments.

A second project, led by Katherine Mathews, director of the MDA clinic at the university, will concentrate on type 2I limb-girdle MD. A third project, led by Baoli Yang, assistant professor of obstetrics and gynecology, will explore the possible use of stem cells to treat muscular dystrophies.

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Consortium to develop new DMD treatment

MDA will join the pharmaceutical company GlaxoSmithKline and other parties to develop an exon skipping strategy as an experimental treatment for Duchenne muscular dystrophy (DMD).

Antisense Compound
Exon Skipping: As a cell prepares the final version of instructions for making a protein, it removes excess material and leaves only the exons, the parts that will form the final protein recipe. Laboratory-designed antisense compounds can make a cell eliminate a specific exon along with the other unwanted material.

Exon skipping (see "Changing the Code," March-April) is designed to coax cells to reinterpret genetic instructions and manufacture normal or nearly normal versions of necessary proteins that they lack.

Some people with DMD have the type of genetic mutation that lends itself to treatment via exon skipping with antisense oligonucleotides or similar laboratory-developed compounds that target and block certain parts of the dystrophin gene.

Dystrophin is the protein that's needed but missing in DMD.

If an antisense compound blocks the mutation in the dystrophin gene, the cell should theoretically synthesize a nearly full-length dystrophin protein molecule, minus the mutated part.

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Respiratory training helps mice with DMD

Researchers at Arnaud de Villeneuve Hospital in Montpellier, France, have found that exposing mice with a disease that resembles Duchenne muscular dystrophy (DMD) to excess carbon dioxide leads to increases in the strength of the respiratory diaphragm and in the amount of alpha-dystrobrevin, a muscle protein.

Stefan Matecki and colleagues, who published their results in the June issue of Neuromuscular Disorders, exposed normal mice and dystrophin-deficient (mdx) mice to excess carbon dioxide for 30 minutes a day over six weeks, causing them to increase their breathing rates.

In the dystrophin-deficient mice, the carbon dioxide exposure training increased the strength of the respiratory diaphragm, although it didn't affect the diaphragm's resistance to fatigue. It had no effect on diaphragm strength or resistance in the normal mice.

The researchers also found increased production of alpha-dystrobrevin, which is normally situated near dystrophin in the muscle cell membrane, in both types of mice. The significance of this increase isn't clear.

The researchers say this type of diaphragm training may be useful in preserving respiratory muscle function in people with DMD.

George Karpati
George Karpati
Louis Kunkel
Louis Kunkel, in front of the original DMD gene diagram

They note, however, that experiments in mice are needed to determine whether the benefit was caused by the increased protein or other effects.

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Grantees honored

Louis Kunkel, professor of pediatrics and genetics at Harvard Medical School in Boston and an MDA grantee since the 1980s, has received the 2004 William Allan Award of the American Society of Human Genetics. Kunkel's MDA-funded team identified the gene that underlies Duchenne muscular dystrophy in 1986.

The award, named for one of the first U.S. physicians to conduct research in human genetics, is presented for substantial and far-reaching scientific contributions carried out over a sustained period of inquiry and productivity.

In June, George Karpati, senior neurologist at the Montreal Neurological Institute and Hospital, became a knight of the Ordre National du Quebec (National Order of Quebec), for outstanding contributions to the development of Quebec society.

Karpati is a professor of neurology at McGill University in Montreal, and a longtime MDA research grantee studying Duchenne MD.

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