Research Updates July-August 2004

Article Highlights:

The latest research news as of June 2004

by Margaret Wahl on July 1, 2004 - 4:26pm

Vitamin C aids CMT1A mice

High doses of ascorbic acid (vitamin C) can improve or stabilize motor function in mice with a particular form of Charcot-Marie-Tooth (CMT) disease, say researchers in France, who published their results in the April issue of Nature Medicine.

Edith Passage and Jean Chretien Norreel at the Institute of Health and Medical Research in Marseilles, and colleagues, gave high doses of ascorbic acid to mice with CMT type 1A, a form of CMT that results from abnormalities in the PMP22 protein (peripheral myelin protein 22).

The human form of CMT1A usually results from a duplication in the gene for PMP22 on chromosome 17, with consequent overproduction of PMP22. It's this type of defect that the researchers reproduced in the mice used in these experiments.

In addition to the improved function, they found evidence that the ascorbic acid may have reduced PMP22 overproduction and thereby normalized the formation of myelin, a sheath that surrounds nerve fibers and helps signals move through the nervous system. The effect may be specific to the type of CMT that results from PMP22 overproduction.

The investigators say they plan to begin clinical trials of vitamin C in CMT1A in the near future, but they urge caution for the present.

Michel Fontes, who was on the study team, said, "We do not know if ascorbic acid works in humans and what the optimal dose is." Fontes went on to say that mice synthesize ascorbic acid, whereas humans don't.

He also expressed concern that if enough patients begin taking large doses of vitamin C on their own, it might be impossible to do a study to find out whether it really works and what its toxicity might be.

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Gene found for CMT2A

A second gene that, when flawed, leads to CMT type 2A, has been identified. A multinational research group that studied seven families from varying ethnic backgrounds with this form of the disease published its results online in Nature Genetics on April 4.

In type 2 forms of CMT, the primary problem is thought to be in the nerve fiber itself, rather than in its myelin sheath, the site of the problem in the type 1 forms.

The new gene, located on chromosome 1, is for a protein called mitofusin 2 (MFN2), which plays a role in the behavior of mitochondria, the energy-producing units of cells and crucial contributors to the health of the nervous system.

Previous research identified the gene for the protein known as kinesin 1B (KIF1B) as a culprit gene for CMT2A in one Japanese family, but so far the MFN2 gene appears to be the more common cause of the disorder.

"We conclude that mutations in MFN2 are the primary cause underlying CMT2A," the investigators say in their paper. "The present study demonstrates a new mechanism for axonal [nerve fiber] neuropathies [nerve diseases] and should provide insight into the pathophysiology of neuropathic disease, both hereditary and acquired."

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Biotech firm to develop gene therapy for Duchenne

Xiao Xiao
Virus-carrying DNA
Virus carrying DNA

MDA has awarded $1.6 million to the North Carolina biotechnology company Asklepios to develop gene therapy for Duchenne muscular dystrophy (DMD). Researchers Richard Jude Samulski, director of the Gene Therapy Center of the University of North Carolina at Chapel Hill, and Xiao Xiao, an MDA grantee and biologist in the Department of Molecular Genetics & Biochemistry at the University of Pittsburgh, are on the Asklepios team.

The company plans to develop and test a virus-based system designed to deliver a miniaturized dystrophin gene to the muscles of boys with DMD. Dystrophin is the muscle protein that's needed but missing in this disease.

After extensive toxicology testing required by the U.S. Food and Drug Administration, the company plans to conduct a phase 1 clinical trial to test the safety of the compound in a small number of DMD-affected boys.


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Naked DNA strategies advance for DMD treatment

MDA grantee Jon Wolff in the Department of Pediatrics at the University of Wisconsin Madison was on a team that announced at a June 2-6 meeting of the American Society of Gene Therapy that it had made significant progress in its intravascular approach to muscle gene transfer.

Wolff is working closely with Mirus, a Madison-based biotechnology company that he co-founded and of which he is chief scientific officer.

Jon Wolff
Jon Wolff

Naked DNA

Naked DNA

Instead of using viruses to transport the genes, Wolff and colleagues injected full-length, human dystrophin genes without viruses — "naked" DNA — into a leg vein in four dystrophin-deficient mice (an animal model for Duchenne MD). They applied a tourniquet around the upper leg of each animal to keep the injected genes concentrated in one area and targeted to that region's muscles.

The researchers found that 3 percent to 15 percent of the leg muscle fibers in the mice showed dystrophin production, while the expected percentage of dystrophin-producing fibers in these animals would be below 0.5 percent. The muscle groups in the back of the upper leg showed the highest average dystrophin presence.

The investigators say the delivery method appears safe and effective and doesn't seem to provoke an unwanted immune response, as viral delivery sometimes does.

They've also experimented with other genes and with a compound called siRNA that can block unwanted gene activity. These experiments, including ones in larger mammals, such as dogs and monkeys, have also shown positive results.

Last year, the French Association Against Muscle Diseases (AFM), in conjunction with the biotechnology company Transgene, of Strasbourg, France, announced that naked DNA showed promise when it was injected into the muscles (not the blood vessels) of 15 boys with DMD or the closely related Becker MD.

A small amount of dystrophin protein was apparently produced from the naked DNA construct, resulting in dystrophin showing up in between 1 percent and 10 percent of injected muscle fibers in the boys who received the highest dose of the construct. (See "Naked DNA," July-August 2003.) The researchers said the experiment showed the construct is safe.

The intravascular approach is designed to increase the number of muscle fibers showing dystrophin per injection of DNA.

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MDA, others explore value of steroid use in DMD

Chris Johnson

MDA is supporting a study of high-dose, weekly prednisone in Duchenne muscular dystrophy, compared to moderate-dose, daily prednisone. The study, being conducted at several sites across the country, still needs participants.

For more information, contact study coordinator Erik Henricson in Washington at (202) 884-3813 or

A national clinical trials network, established by MDA in June, will likely further investigate the use of corticosteroids in DMD.

This spring, two groups published reports of their preliminary conclusions on the use of corticosteroids in (DMD), with recommendations for further action.

Corticosteroids such as prednisone, prednisolone and deflazacort (outside the United States) are commonly prescribed to prolong walking in youngsters with DMD. So far, though, there hasn't been a consensus on the optimal usage of these medications.

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ENMC report

A group of 35 participants from several European countries, the United States, Britain and Canada convened in Naarden, the Netherlands, April 2-4, to discuss new directions for corticosteroid use in DMD. Among them was Sharon Hesterlee, MDA's director of research development.

In a report that can be read in its entirety on the ENMC Web site at, the group concluded that there can "no longer be any doubt that the use of steroids in ambulant [walking] children with DMD alters the natural history of the condition."

The report also said that:

  • children treated with daily steroids are likely to walk for longer, have improved respiratory function, may avoid the need for spinal surgery and might have better heart function than untreated children;
  • there are significant side effects associated with prednisone and deflazacort;
  • alternatives to daily steroid dosages might mitigate side effects and still provide benefits;
  • a large-scale clinical trial to test different approaches to steroid use is urgently needed;
  • and, pending new information, boys with DMD on steroids should be as active as possible, maintain proper levels of vitamin D and calcium to minimize bone loss, and avoid sweets and fast foods to control their weight.

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Cochrane review

Also published this spring is the Cochrane Collaboration's review of multiple studies of corticosteroids in DMD.

The Cochrane Collaboration is a not-for-profit organization that publishes quarterly reports on health care interventions based primarily on analyses of randomized clinical trials — those in which participants with the same characteristics are randomly assigned to a treatment or nontreatment group and then compared.

Summaries of these reviews are available at, and complete reviews are available for purchase through the Web site.

In issue 2, 2004, of the Cochrane Library, the reviewers discuss corticosteroids for DMD, basing their analysis on five randomized trials.

They found that:

  • corticosteroids improve or stabilize muscle strength and function for six months to two years;
  • the most effective dose of prednisone or prednisolone appears to be 0.75 milligrams per kilogram per day;
  • adverse effects, such as excessive weight gain, behavioral abnormalities, redistribution of body fat to the face and abdomen, and excessive hair growth, are significantly more common in those taking steroids but are not severe;
  • the long-term benefits and hazards of corticosteroids in DMD can't be evaluated from published studies;
  • nonrandomized studies support the conclusions of functional benefits but also indicate significant adverse effects with long-term steroid treatment;
  • and more studies are needed.

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