Research Updates July-August 2008

Article Highlights:

The latest research updates as of June 2008

by Quest Staff on July 1, 2008 - 1:37pm

QUEST Vol. 15, No. 4

This article includes items on: Duchenne muscular dystrophy, myotubular myopathy, acid maltase deficiency, spinal muscular atrophy, genetic information, limb-girdle muscular dystrophy, congenital muscular dystrophy, translational research

A little dystrophin is better than none

MDA grantee Dongsheng Duan at the University of Missouri at Columbia, and colleagues, have found that mice with only 5 percent of the normal level of the muscle protein dystrophin were slightly stronger, at least temporarily, than mice without any dystrophin.

The study, published online April 1 in the American Journal of Pathology, may have implications for potential gene-based and other therapies for Duchenne muscular dystrophy (DMD) that only partially restore the needed dystrophin protein to muscles.

Until now, it’s been assumed by most experts that about 20 percent of the normal level of dystrophin would be needed for therapy to be meaningful in boys with DMD, a disease in which dystrophin is missing in muscle cells.

But when Duan’s team bred mice that not only had very low dystrophin levels but made a slightly smaller-than-normal version of the protein, they were surprised to see stronger grip strength and more resistance to contraction-related injury than they did in mice without any dystrophin at all. However, they also noted the muscle protection was limited and wore off when the mice got old.

In humans, the researchers note, 30 percent of a normal dystrophin amount is thought to be sufficient to prevent MD, and 20 percent has been believed to result in mild MD. It now appears that levels perhaps even as low as 5 percent of normal might be beneficial, even if they aren’t curative.

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Gene transfer may be a good way to block myostatin

Transferring the gene for a myostatin-blocking protein into muscles might be a good way to block this muscle-growth-limiting protein, say researchers coordinated by Xiao Xiao at the University of North Carolina at Chapel Hill, in a report published in the March issue of Human Gene Therapy.

Various compounds to inhibit myostatin have been proposed as possible treatments for muscle degeneration, and one such compound, MYO-029, recently was tested in a clinical trial in adults with various muscular dystrophies. MYO-029 is an immune-system protein (antibody) that blocks, or neutralizes, myostatin. It was found safe in patients. (See Research Updates, May-June 2008).

Xiao and colleagues inserted the gene for MPRO (myostatin propeptide), which blocks myostatin, into the shells of type 8 adeno-associated virus (AAV8). They then injected the AAV8-MPRO combination into a vein in mice with Duchenne muscular dystrophy (DMD).

After only one injection into each mouse, they saw an increase in skeletal muscle bulk and strength, as well as larger and more uniform muscle fibers and less inflammation and scar tissue than in untreated DMD-affected mice.

However, on a treadmill test, the treated mice showed less endurance than their untreated counterparts. The investigators say they have no clear explanation for this, but they note that stronger muscle force doesn’t necessarily mean better endurance and that blood-vessel abnormalities in these mice also might be a contributing factor.

Xiao, who has received MDA funding for other gene-transfer research, says the long-lasting nature of a gene transfer approach is an advantage over using an antibody or other protein. “Since we used AAV to produce the propeptide in a continuous way in the mice, any newly synthesized myostatin in muscle will be neutralized,” he said.

“When you use a neutralizing [disabling] antibody against myostatin, you have to keep administering it to the patients frequently to keep an effective concentration required to block myostatin activity. When using a gene therapy approach with AAV, the mice — or patients — produce their own propeptide 24 hours a day, seven days a week.”

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Gene transfer benefits mice with myotubular myopathy

Anna Buj-Bello at Louis Pasteur University in Illkirch, France, with a team that included MDA grantee Alan Beggs at Children’s Hospital and Harvard Medical School in Boston, have demonstrated that gene transfer may be an effective approach to treating myotubular myopathy (MTM), which results from the lack of a protein called myotubularin.

Chaperone molecules like the one Amicus Therapeutics is developing for Pompe disease help damaged or malformed proteins fold into a usable shape.

A single injection of myotubularin genes into a leg muscle in myotubularin-deficient mice resulted in a large increase in muscle volume and force, as well as a normalization of microscopic appearance of the muscle fibers in the injected muscle.

The researchers, who published their results online April 22 in Human Molecular Genetics, used modified adeno-associated viruses (AAVs) as delivery vehicles for the genes. AAV vehicles have been used in human gene-transfer trials to target muscle fibers.

They note that their results “indicate that gene therapy by local [myotubularin] transfer in skeletal muscle improves the strength of the targeted muscle in a mouse model of myotubular myopathy and might open novel strategies for treating this disorder.”

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Protecting mitochondria with Debio-025 helped mice with two forms of MD

A compound that protects cellular structures known as mitochondria from damage is beneficial in mice with two forms of muscular dystrophy, investigators have found.

Jeffery Molkentin at Cincinnati Children’s Hospital Medical Center, and colleagues, including H. Lee Sweeney at the University of Pennsylvania, who has MDA funding for related work, published their findings online March 16 in Nature Medicine.

First, the investigators analyzed mice with two forms of MD that also were bred not to produce a protein called cyclophilin D.

The lack of cyclophilin D prevented much of the damage that would have been expected in the delta-sarcoglycan-deficient mouse model of type 2F limb-girdle MD (LGMD2F) and the laminin-2-deficient mouse model of congenital MD. This is due to its apparent protection of mitochondria, the energy-producing structures inside cells.

In both these forms of MD, as well as in Duchenne MD (DMD), the membrane surrounding each muscle fiber allows excess calcium to flow into muscle cells, which, in part through cyclophilin D’s actions, causes swelling and destruction of mitochondria. Without cyclophilin D, the researchers found, the mitochondria of MD-affected mice demonstrated resistance to this type of damage.

They next tested Debio-025 (made by DebioPharm of Lausanne, Switzerland), a known inhibitor of cyclophilin D, in the mouse model of LGMD2F and in mice missing the dystrophin protein that have a disease resembling DMD.

The mitochondria of these mice also were protected. In addition, the DMD mice treated with Debio-025 from four to 10 weeks of age showed better muscle-fiber organization and less scar tissue than was seen in untreated DMD mice.

Similar effects were seen in the LGMD2F mice treated with Debio-025 from age four to age 10 weeks, and these mice also showed better cardiac muscle health than did untreated LGMD2F mice.The researchers say their results suggest that protecting muscle-fiber mitochondria by inhibiting cyclophilin D could become a new approach for treating muscular dystrophies that are associated with defective muscle-fiber membranes.

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Company to develop ‘chaperone’ molecule for Pompe disease

A new approach to treating Pompe disease (acid maltase deficiency), a genetic muscle disorder resulting from a lack of functional acid maltase enzyme, has yielded encouraging findings to researchers at Amicus Therapeutics, a biopharmaceutical company in Cranbury, N.J.

The company presented results of tests in patients’ cells and in healthy volunteers of its experimental compound AT2220 at the American College of Human Genetics annual meeting in Phoenix in March. (Amicus presented an earlier stage of its research to MDA’s Translational Research Advisory Committee.)

AT2220 is a small, orally administered molecule that Amicus terms a “pharmacological chaperone,” one of several the company is developing to treat genetic diseases.

Pharmacological chaperones, like their natural counterparts in cells, stick to specific proteins and help them fold into the correct three-dimensional shape. Many genetic diseases, including Pompe disease, can be caused at least some of the time by genetic mutations that result in improper folding of a protein. (In Pompe disease, the protein is the acid maltase enzyme, made from the acid maltase gene.) An improperly folded enzyme doesn’t locate itself or function properly.

The Amicus researchers collected blood and skin samples from 30 people with Pompe disease (26 adults, three children and one infant) due to a variety of mutations in the acid maltase gene.

They then tested cells from these samples to see whether AT2220 could increase the level of functional acid maltase.

Of 26 patients analyzed, 24 had cells that responded to the experimental treatment.

The company also tested AT2220 in 72 healthy volunteers and found it to be safe and well tolerated at all doses studied.

In November, Amicus announced it plans to further develop AT2220 in partnership with Shire Human Genetic Therapies, part of the multinational Shire biopharmaceutical company (

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MDA, SMA groups release family version of SMA Standard of Care

The Patient Advisory Group of the International Coordinating Committee (ICC) for SMA Clinical Trials has published a family-friendly set of guidelines for care in spinal muscular atrophy (SMA) to complement the physician guidelines published in August. (See Research Updates, November-December 2007.)

The ICC includes representatives of MDA, the SMA Foundation, FightSMA and Families of SMA.

The new publication, “A Family Guide to the Consensus Statement for Standard of Care in Spinal Muscular Atrophy,” is designed to guide patients and families in their discussions with doctors and health-care specialists. The committee emphasizes that these guidelines are only suggestions and should not be considered absolute requirements for care.

The Guide has recommendations on confirming the diagnosis; managing breathing, eating and nutrition, movement and daily activities; and preparing for illness.

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MDA joins SMA groups in support of SMA Treatment Acceleration Act

MDA has joined the SMA Foundation, Families of SMA, and FightSMA in endorsing the SMA Treatment Acceleration Act (H.R. 3334/S.2042). The Act, if passed by Congress, will aid investigators in conducting national clinical trials to identify treatments for spinal muscular atrophy (SMA). It would provide federal support to complement the substantial private funding that national nonprofit organizations, including MDA, are now providing.

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GINA gets thumbs-up from Congress

Under the provisions of legislation approved by Congress this spring, insurance companies now are prohibited from requiring people to undergo genetic tests, and from denying them health care insurance or increasing their premiums based on genetic test results.

The Genetic Information Nondiscrimination Act (GINA) also prohibits employers from using genetic test results when making hiring, compensation, assignment or promotion decisions.

President George Bush signed the act on May 21.

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