Research Updates January-February 2006

Article Highlights:

Updates on research as of December 2005

by Margaret Wahl on January 1, 2006 - 2:54pm

QUEST Vol. 13, No. 1

Featured in this article:  Early diagnosis improves cardiac outlook in DMD, BMD * Heart damage and dystrophin mutation * Frataxin in Friedreich's * Progress in MD gene therapy * Split gene strategy * Toxic RNA destroyed in myotonic MD * LGMD gene saves hamster hearts * Three new MD centers named * Rando receives NIH Pioneer Award * MDA supports easing biotech restrictions

Shane Bourque
Boys with Becker MD, like Shane Bourque, and Duchenne MD may benefit from the new research on cardiac treatment.

Early diagnosis, treatment improve cardiac outlook in Duchenne, Becker MDs

A research group at Baylor College of Medicine and Texas Children’s Hospital in Houston has found that early diagnosis and treatment of the most common type of heart problem found in Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) can markedly improve the course of this abnormality, which is called dilated cardiomyopathy.

Benefits of early treatment of other types of cardiomyopathy have been shown. But this study and one by a French group (see “Research Updates,” May-June 2005) provide the first hard data that the same approach could make a significant difference in this life-threatening complication of MD.

The Baylor study was coordinated by Jeffrey Towbin, a pediatric cardiologist and consultant to the MDA clinic in Houston, and published in the Nov. 1 issue of Circulation.

In the study, 62 boys with DMD and seven with BMD who were referred to a cardiac clinic for evaluation were included, regardless of whether they had any indications of cardiac impairment. Of these, 31 developed cardiac damage. The average age at onset was approximately 15, although some children were as young as 10.

The 31 boys who showed abnormalities on an echocardiogram (imaging study of the heart) were given an angiotensin-converting enzyme (ACE) inhibitor medication. In those who didn’t show improvement in three months, a beta blocker was added. ACE inhibitors reduce the pressure against which the heart has to pump, and beta blockers slow the heart rate.

Jeffrey Towbin
Jeffrey Towbin

After about three years of treatment, 27 of 29 of the boys (93 percent) showed either improvement or stabilization of their dilated cardiomyopathy. Eight DMD-affected participants showed improvement (toward normal) in heart size, function or both; 19 (16 with DMD and three with BMD) had a normal heart size, function or both; and two, both with DMD, had stable heart function and size, with no deterioration over the study period.

“We think that the combination of our study plus Duboc’s study [from France] is strong support for the fact that early treatment, either predating the onset by echocardiogram of disease, or as early as you can get the onset of disease, is a good thing and worth doing,” Towbin said.

“And it suggests testing the hypothesis, in a large study, that preclinical therapy is a good idea. You might want to treat patients at age 8 or 10, before they have problems from a cardiovascular standpoint, and see how late you could push the age of onset.”

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Heart damage varies with dystrophin mutation

The Baylor team that studied ACE inhibitors and beta blockers in cardiomyopathy (see “Early Diagnosis” above) also found that certain mutations (DNA errors) in the gene for dystrophin are more likely than others to lead to heart disease. Dystrophin is the skeletal and heart muscle protein entirely missing in Duchenne muscular dystrophy muscle cells and partly deficient in Becker MD cells.

The researchers found that mutations affecting the area of the dystrophin gene known as exons 12 and exons 14 to 17, as well as mutations in exons 31 to 42, seem to be particularly associated with heart disease. Boys with mutations in exons 51 or 52 had a lower risk of cardiac involvement. In their Nov. 1 paper in Circulation, researchers say these findings should be considered preliminary because of the small sample size.

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Protein may increase frataxin in Friedreich’s ataxia

The protein erythropoietin, known mostly for its ability to boost red blood cell production, has been found to have another, previously unsuspected action: It increases levels of the protein frataxin, which is deficient in people with Friedreich’s ataxia (FA), and might provide a direction for future drug development for that disease. Erythropoietin is now used to treat patients with kidney failure who are undergoing dialysis.

Barbara Scheiber-Mojdehkar, a chemist and MDA grantee at the Medical University of Vienna (Austria), headed a research team that administered erythropoietin to white blood cells taken from people with FA, and to cardiac muscle cells, connective tissue cells and nerve cells obtained from other sources. In all cases, increased frataxin levels were correlated with erythropoietin administration.

The study’s authors, who published their results in the November issue of the European Journal of Clinical Investigation, write that there is now a “scientific basis for examining the effectiveness of this agent for the treatment of Friedreich’s ataxia patients.”

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Treatments involving the insertion of therapeutic genes or the blocking of toxic ones have been slower to develop than scientists and families had hoped, but safer delivery methods and better understanding of the molecular basis of diseases have recently quickened the pace of gene therapy development.

At a meeting of the International Myotonic Dystrophy Consortium held in Quebec in October, MDA grantee Jack Puymirat, a neurologist and molecular biologist at Laval University in Quebec, presented results of the first successful experiments to directly combat toxic genetic material in type 1 myotonic dystrophy (MMD1) in animals.

Jack Puymirat, of Laval University, Quebec
Jack Puymirat, of Laval University, Quebec

Puymirat, with colleagues in France, gave mice with type 1 MMD two molecular therapies, both of which were effective in reducing the amount of extra RNA in the cells. The mice had extra DNA on chromosome 19, resulting in extra RNA stuck in their cell nuclei — the main cause of MMD1.

In one set of experiments, the investigators gave the mice an RNA-cutting enzyme called a ribozyme, delivered in the shell of an adeno-associated virus (AAV). In another, they gave the mice an antisense compound, which targeted the extra RNA and attracted innate cellular mechanisms that destroyed it.

Puymirat said he hopes clinical trials of a potential human treatment will begin in about three years.

Xiao Xiao
Xiao Xiao

MDA grantees Xiao Xiao and Chunping Qiao at the University of Pittsburgh were part of a research team that recently announced it had successfully transferred genes for delta-sarcoglycan to hamsters missing this skeletal and cardiac muscle protein, significantly improving their cardiac and whole-body functioning and ex-tending their lives.

A lack of any of four sarcoglycan proteins, normally found in the membranes of muscle cells, leads to sarcoglycan-deficient limb-girdle muscular dystrophy (LGMD) in humans.

In a study published in the Oct. 25 issue of Circulation, Xiao and colleagues report that they gave delta-sarcoglycan genes, encased in type 8 adeno-associated virus (AAV8) shells, to LGMD-affected hamsters, by injecting the genes only once into the abdomen or into a vein.

Even months later, heart function and appearance, along with the ability to run on a treadmill, were markedly better than in an untreated group, and all the treated hamsters were alive at the end of the nearly yearlong study.

Chunping Qiao
Chunping Qiao

The researchers found that the AAV8 shell was extremely effective in delivering the therapeutic genes to heart, diaphragm and skeletal muscles but that it also delivered them to other tissues. They say they overcame this problem by attaching a muscle-specific “on switch” (promoter) to the gene, so that delta-sarcoglycan wouldn’t accumulate in unwanted tissues, such as the liver. Even adult animals, with mature immune systems, didn’t reject the therapeutic gene or protein.

The study’s authors write, “The unprecedented gene delivery efficiency and therapeutic efficacy for both cardiomyopathy and muscular dystrophy demonstrated here in an animal model should pave the way for further preclinical studies... and eventually in clinical trials for this and other genetic diseases.”

Dongsheng Duan
Dongsheng Duan
Jeffrey Chamberlain
Jeffrey Chamberlain

MDA grantees Dongsheng Duan at the University of Missouri-Columbia and Jeffrey Chamberlain at the University of Washington-Seattle were on a research team that recently used a new strategy to deliver genes for dystrophin, the muscle protein missing in Duchenne muscular dystrophy (DMD), to dystrophin-deficient mice with a DMD-like disorder.

The dystrophin protein is made from an extremely large gene, which has to be downsized to fit into a viral shell that can deliver it to muscles. Other MDA-supported groups, including one led by Chamberlain, are pursuing gene therapy with highly miniaturized (micro) dystrophin genes.

Shortened but functional dystrophin protein molecules can be made from these microgenes, but it’s still uncertain how much impact these microdystrophins will have on Duchenne dystrophy.

Now, Duan and Chamberlain’s team, which published its results in the November issue of Nature Biotechnology, has found that longer (mini instead of micro) dystrophin molecules can be made if the gene is split into two specially engineered pieces. Each piece is placed in a separate viral transporter, and they rejoin after they emerge from their shells.

The researchers inserted each gene segment into a modified type 6 adeno-associated virus (AAV6) shell and injected both loaded shells into leg muscles of the DMD-affected mice.

In 2-month-old mice, minidystrophin molecules showed up in more than half of the muscle fibers in the injected areas, where they protected fibers from injury and increased their force-generating capacity.

In 1-year-old mice, an average of 40 percent of the fibers produced minidystrophin, but resistance to injury wasn’t as good as in the 2-month-olds.

The investigators say the split gene strategy may have important implications for delivering not only dystrophin but other genes that are too large to fit into an AAV shell. They also say the results suggest that gene transfer may be more effective in younger patients, although it might still be somewhat effective in older ones.

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NIH names three new MD centers of excellence

As a result of the passage of the 2001 MD-CARE Act, Congress mandated that the National Institutes of Health (NIH) establish and fund several “centers of excellence” for muscular dystrophy research. Three such centers, at the University of Washington-Seattle, the University of Rochester (N.Y.) and the University of Pittsburgh, were awarded grants from both NIH and MDA shortly thereafter and are now known as Sen. Paul D. Wellstone Muscular Dystrophy Cooperative Research Centers.

Recently the NIH has designated three additional Wellstone centers. They’re at the University of Iowa in Iowa City, Children’s National Medical Center in Washington, D.C., and the University of Pennsylvania in Philadelphia.

All Wellstone centers involve MDA research grantees and emphasize biomedical research projects with relevance to muscular dystrophy treatment.

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MDA grantee receives NIH Pioneer Award

Tom Rando
Tom Rando is working on nonvital gene delivery methods.

MDA research grantee Thomas Rando, an associate professor in the Department of Neurology and Neurological Sciences at Stanford (Calif.) University, has received a 2005 Pioneer Award from the National Institutes of Health (NIH).

The NIH Pioneer Award goes to exceptionally creative scientists who take innovative approaches to major challenges in biomedical research, supporting them with up to $500,000 per year for five years. Thirteen such awards were given out in 2005.

Rando, who’s developing gene therapy for Duchenne muscular dystrophy that doesn’t involve viral delivery vehicles, is also working on stem cells in tissue repair and regeneration, and has worked on gene repair strategies.

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MDA supports bill to ease biotech restrictions

MDA has joined some 30 other organizations that fund medical research in urging Congress to ease restrictions on small business loans for new biotechnology companies.

Recent changes in the government’s Small Business Administration grants program have excluded companies that rely heavily on outside investors (venture capitalists), which describes most biotech startup firms. The Biotechnology Industry Organization (BIO) is sponsoring a bill (H.R. 2943 and S.1263) to lift this restriction.

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