Research Updates Summer 2011

Article Highlights:

The latest research news as of June 2011:

by Quest Staff on July 1, 2011 - 1:01pm

QUEST Vol. 18, No. 3

New CMS-causing genetic mutations indentified

Scientists supported in part by MDA have identified mutations in the gene for the plectin protein as a rare cause of a congenital myasthenic syndrome (CMS).

Congenital myasthenic syndromes can be caused by a number of different genetic mutations, all of which affect signaling at the neuromuscular junction, where nerve and muscle fibers meet. MDA supported Andrew Engel at the Mayo Clinic in Rochester, Minn., for this work, which was published January 25, 2011, in Neurology.

In a separate study, published February 11, 2011, in the American Journal of Human Genetics, a multinational team of scientists identified mutations in the gene for the glutamine-fructose-6-phosphate transaminase 1 (GFPT1) protein as underlying other forms of CMS.

The GFPT1 protein, an enzyme, regulates glucose (sugar) levels throughout the hexosamine pathway. Disruption of its function affects signaling at the neuromuscular junction.

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DMD, LGMD2F: Raising SERCA1 protein levels beneficial in mice

A team of U.S. researchers has found that raising levels of a protein called SERCA1 in skeletal muscles results in dramatic improvement of symptoms in mice with diseases resembling Duchenne muscular dystrophy (DMD) or the type2F form of limb-girdle muscular dystrophy (LGMD2F). Mice bred to produce extra SERCA1 were compared with mouse models of DMD and LGMD2F that were not bred to produce high levels of this protein.

SERCA1 helps reduce calcium levels inside muscle fibers by pumping calcium into sequestered storage areas in the fibers.

The results, published March 1, 2011, in the Journal of Clinical Investigation, suggest that various calcium-modifying therapies, including perhaps gene therapy with the gene for a SERCA1 or a similar SERCA protein, might be beneficial in some forms of MD.

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Zebrafish screen provides three new leads for DMD, BMD

Three interesting drug candidates have been identified from among more than 1,120 chemicals screened in dystrophin-deficient zebrafish.

Zebrafish provide a good system for drug screening.

The three candidates all lengthened survival time and improved muscle function in the fish, which lacked the same muscle protein that’s deficient in Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD).

Zebrafish have been found to be a good system for drug screening, as they’re transparent, permeable to chemicals in their water environment and fairly inexpensive to maintain.

MDA research grantee Louis Kunkel at Children’s Hospital Boston and Harvard Medical School led the study team, which published its results online March 14, 2011, in Proceedings of the National Academy of Sciences USA.

The researchers started with a commercial library of chemicals, 90 percent of which already are on the market as medications. They then narrowed the number of potentially beneficial chemicals to three:

  • an anti-inflammatory agent called epirizole;
  • a chelating (chemical binding) agent called pentetic acid; and
  • aminophylline, which is used to treat asthma.

The three lead chemicals all conferred survival advantages on the dystrophin-deficient fish, with aminophylline resulting in the largest survival effect. All surviving fish treated with the three front-running chemicals appeared to move normally, and all showed normal muscle structure.

Interestingly, none of three chemicals restored dystrophin production, however, indicating that the treatments allowed the zebrafish muscles to develop normal structure and function despite their lack of dystrophin.

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Joe Sarsero
Joseph Sarsero at Royal Children's Hospital in Parkville, Australia, was part of the team that improved frataxin gene analysis.

Improved technique detects interruptions in frataxin gene expansions in FA

Investigators in Australia, supported in part by MDA, have developed a new technique that they describe as “simple and rapid” for determining the presence of interruptions in the expanded section of DNA in the frataxin gene that causes Friedreich’s ataxia (FA).

There is evidence that interruptions in the disease-causing DNA expansion lessen the severity of the disease course. The findings were published in March 2011 in BioTechniques.

MDA supported Joseph Sarsero at Royal Children’s Hospital in Parkville, Victoria, Australia, for this work.


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Ultragenyx Pharmaceutical working on drug to treat hereditary IBM

Ultragenyx Pharmaceutical in Novato, Calif., is developing an experimental treatment for a form of hereditary inclusion-body myositis or hIBM (also known as inclusion-body myopathy) that’s caused by mutations in the GNE gene.

This gene codes for a protein that’s needed to make sialic acid. The Ultragenyx product, an extended-release form of sialic acid, is not yet in clinical trials.

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Dystroglycan gene mutation can cause LGMD with severe cognitive impairment

Scientists have found that a mutation in the gene for the muscle protein dystroglycan can cause limb-girdle muscular dystrophy (LGMD) with severe cognitive impairment. MD-causing mutations in the dystroglycan gene have not been previously identified, although mutations in several genes that interact with dystroglycan are known to cause LGMD or congenital muscular dystrophy (CMD).

The findings were published March 10, 2011, in the New England Journal of Medicine. Kevin Campbell at the University of Iowa, who has MDA support for closely related work, coordinated the study team.

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GM-CSF in development to tame immune system in MG

A compound called GM-CSF, designed to rebalance the misbehaving immune system in myasthenia gravis (MG), will be tested in mice with an MG-like disease and later in a small group of people with MG. The project is the result of an MDA grant to Matthew Meriggioli at the University of Illinois-Chicago.

The goal is to use GM-CSF in MG to stimulate proliferation of regulatory immune system cells that dampen the unwanted immune system attack that occurs in this disease. In most people with MG, weakness occurs because the immune system mistakenly attacks structures called acetylcholine receptors on muscle fibers, interfering with the ability of the muscle fibers to receive signals from the nervous system.

A GM-CSF-based drug called sargramostim (brand name Leukine) has been approved by the U.S. Food and Drug Administration for use following chemotherapy or bone marrow transplantation for blood-cell cancers.

In these circumstances, GM-CSF is used to stimulate recovery of the immune system after damage from cancer treatment. The fact that Leukine is already on the market may save some steps in the approval process.

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Mice with SMA-like disease benefit from antisense molecule

Adrian Krainer
Adrian Krainer at Cold Spring Harbor (N.Y.) Laboratory received recent MDA support to develop antisense oligonucleotides as SMA therapies.

Mice with a disease resembling severe spinal muscular atrophy (SMA) that were injected with a synthetic molecule developed bigger, more structurally sound muscles than their untreated counterparts.

The molecule, known as ASO-10-27, is an antisense oligonucleotide, one of a class of experimental drugs designed to change the way cells interpret genetic instructions so that they can produce a functional protein despite a genetic mutation.

In SMA, the goal of ASO-10-27 and other strategies is to coax cells to reinterpret genetic instructions for the SMN protein and make enough functional SMN to improve symptoms.

The findings were published March 2, 2011, in Science Translational Medicine. Adrian Krainer at Cold Spring Harbor (N.Y.) Laboratory, who has received MDA support for closely related work, was part of the study team.


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Motor neurons made from skin cells have implications for SMA research

Motor neurons, the cells affected in spinal muscular atrophy (SMA), can be generated from human skin cells without using viruses, new findings show. These cells may have research and therapeutic possibilites for SMA.

Stefania Corti from the University of Milan (Italy) presented her research group’s findings in April 2011 at the annual meeting of the American Academy of Neurology.

The Italian team obtained skin cells (more specifically, fibroblasts) from an SMA patient and his father, who does not have SMA. The researchers induced these cells to become pluripotent stem cells, (which can become multiple cell types) and from there, to become motor neurons. They used a method that did not leave behind any remnants of the agents used for the cell conversions.

The investigators saw significant differences between the motor neurons derived from the SMA patient and those from his unaffected father, suggesting that the cells derived from the patient developed characteristics of the disease.

They then transplanted the newly formed motor neurons from the patient and those from his father into the spinal cords of SMA research mice. Both types of cells increased the life span of the mice. However, fewer cells from the SMA patient engrafted into the mouse spinal cords compared to cells from his father.

Motor neurons made from skin cells could have multiple implications for research and therapies.

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Christopher Rosa
Christopher Rosa, who has Becker MD and wrote a doctoral dissertation on disability culture, will speak at the August 2011 conference.

MDA, in partnership with Cedars-Sinai Medical Center, is sponsoring a one-day conference for families affected by Becker muscular dystrophy (BMD) in Los Angeles on August 13, 2011. The meeting will feature presentations and discussions of daily life issues, research and medical care.

Among the speakers will be Ronald Victor, a cardiovascular specialist and MDA research grantee at Cedars-Sinai; Elizabeth McNally, a cardiologist and MDA research grantee at the University of Chicago Medical Center who serves on MDA’s Scientific Advisory Committee; and Christopher Rosa, University Dean for Student Affairs at the City University of New York, who serves on MDA’s Board of Directors and National Task Force on Public Awareness.

Rosa, who has Becker MD, holds a doctorate in sociology; his dissertation was on the construction of a disability culture.

For more information, contact Annie Kennedy, MDA senior vice president for advocacy, at

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The 2011 MTM-CNM Family Conference sponsored by the Myotubular Myopathy Resource Group will take place July 29-31, 2011, in Minneapolis. The conference is designed to allow families affected by myotubular myopathy (MTM) or other forms of centronuclear myopathy (CNM) to connect with physicians and researchers who have a special interest in these disorders.

For details and registration information, go to the conference home page. Or contact Chrissie Sanders, 7293 Mount Kearsarge Street, Las Vegas, NV 89131; (702) 271-9791.

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