Research Updates Winter 2012

An international, MDA-supported study will identify genetic modifiers of CMT1A and determine additional genetic causes of CMT in general.
Article Highlights:
by Quest Staff on January 1, 2012 - 12:10pm

QUEST Vol. 19, No. 1

Researchers studying ‘natural history’ of four CMT subtypes

Participants are sought for a large-scale study, supported in part by MDA, to determine the natural history (general disease course) of four subtypes of Charcot-Marie-Tooth disease (CMT), with particular emphasis on correlations between genetic mutations and symptoms. The four subtypes are CMT1B, CMT2A, CMT4A and CMT4C.

Neutologist Michael Shy
Neurologist Michael Shy examines a child.

In addition, the investigators are seeking people with any form of CMT for possible inclusion in later studies.

The natural history study is jointly funded by MDA and the National Institute of Neurological Disorders and Stroke (NINDS).

Neurologist and molecular geneticist Michael Shy, a longtime MDA research grantee at Wayne State University in Detroit, is the principal investigator on this study, which is expected to enroll 3,000 people.

For the natural history study of CMT1B, CMT2A, CMT4A and CMT4C, prospective participants must have a mutation in the MPZ gene (for CMT1B); or in the MFN2 gene (for CMT2A); or have a close relative with one of these mutations and signs of CMT; or have two mutations in the GDAP1 gene (for CMT4A); or two mutations in the SH3TC2 gene (for CMT4C); and meet other study criteria.

Genetic testing, in general, is not paid for by the study. Exceptions may be made in some cases.

For possible enrollment in future CMT studies, prospective participants can have any form of CMT and do not need to know their subtype.

U.S. study sites are in Baltimore; Detroit; Rochester, N.Y.; Philadelphia; and Seattle. Contact Carly Siskind in Detroit at (313) 577-8317 or; or Michael Shy at

For details, visit, and enter NCT01193075 into the search box.

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CMT1A and CMT of unknown cause are being studied

Researchers supported in part by MDA are seeking people with Charcot-Marie-Tooth disease (CMT) to participate in a study to identify genetic modifiers of the type 1A form of CMT (CMT1A) and determine previously unknown genetic causes of CMT.

The study is based at Wayne State University in Detroit, under principal investigator and MDA grantee Michael Shy, with additional U.S. sites in Baltimore; Rochester, N.Y.; Philadelphia; and Seattle.

MDA and the National Institute of Neurological Disorders and Stroke (NINDS) have partnered to support this large-scale effort.

Participants in the CMT1A component of the study must have a duplication of the PMP22 gene or signs of CMT and a close relative with this type of genetic mutation; be at least 13 years old; and meet other study criteria.

Participants in the “new causes of CMT” component of the study must have signs of CMT; be at least 13; have negative genetic test results for an MFN2 mutation if an “axonal” form of CMT is suspected; negative test results for mutations in the PMP22, MPZ and GJB1 genes if a “demyelinating” form of the disease is suspected; or have signs of CMT and a close relative whose genetic tests have been negative for these mutations; have at least one additional family member willing to be in the study; and meet other criteria.

The investigators also are seeking people without CMT who are at least 13 years old for participation in a “control” (comparison) group.

Contact Lisa Rowe in Detroit at (313) 577-1689 or For details, enter NCT01193088 into the search box at

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Albuterol improved quality of life in two forms of CMS

Researchers have found that the drug albuterol appears to be beneficial in two forms of congenital myasthenic syndrome (CMS) — CMS related to mutations in the collagen Q (colQ) gene and CMS related to mutations in the DOK7 gene.

MDA funded Andrew Engel, professor of neurology at the Mayo Clinic in Rochester, Minn., for this work. The findings were published in the November 2011 issue of Muscle & Nerve.

The results are from an “open-label” trial in which all participants knew they were taking albuterol. Although this type of trial is not conclusive, Engel said he would “not withhold albuterol from seriously ill patients” with DOK7-related or colQ-related myasthenic syndromes.

Eighteen trial participants ages 5 to 58 received albuterol by mouth for one month to two years and completed questionnaires about their functional abilities. All except one reported an increase in quality of life with this medication, which has U.S. Food and Drug Administration (FDA) approval as a treatment for asthma and other lung disorders. It isn’t clear why the drug helps in CMS.

Some trial participants were able to return to work or school, some no longer required a wheelchair, one no longer needed nighttime ventilation, and one became nearly symptom-free.

One participant experienced an abnormal heart rhythm thought to be related to albuterol.

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PTC remains committed to ataluren for nonsense-mutation DMD/BMD

In September 2011, PTC Therapeutics and Genzyme restructured their agreement regarding development of ataluren for Duchenne and Becker muscular dystrophies (DMD and BMD) caused by so-called nonsense mutations.

PTC regained commercial development rights to ataluren for nonsense-mutation DMD and BMD in all countries and said it remains committed to development of the drug for those diseases.

Nonsense mutations, also known as premature stop codon mutations, cause cells to stop synthesizing a protein before the cell has finished “reading” the genetic instructions (RNA) for the protein. It’s believed that some 5 to 15 percent of people with a DMD or BMD diagnosis have nonsense mutations that prematurely stop synthesis of the dystrophin protein.

People who participated in trials of ataluren for nonsense-mutation DMD/BMD in the United States are eligible to join an open-label safety study of the drug.

Contact Diane Goetz at PTC Therapeutics in South Plainfield, N.J., at (866) 282-5873 or For details and study locations, enter NCT01247207 into the search box at

Participants in previous trials in Canada of ataluren for nonsense-mutation DMD/BMD should contact the study coordinator or principal investigator at their former study site if they wish to participate in an ataluren special access program.

Participants in previous trials outside the United States and Canada should wait to be contacted by their investigators regarding ataluren studies in their countries.

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More GSK2402968 exon-skipping trials planned in DMD

A phase 1 trial of the experimental drug GSK2402968 in nonwalking boys with Duchenne muscular dystrophy (DMD) has completed its enrollment. The trial is being conducted at Nationwide Children’s Hospital in Columbus, Ohio, and in France.

GSK2402968, developed by Prosensa and under license to GlaxoSmithKline, is designed to cause production of the dystrophin protein in boys with DMD who have specific mutations in the dystrophin gene. It causes muscle cells to ignore (skip) a section of the dystrophin gene called exon 51 and piece together remaining genetic instructions for dystrophin. (See Exon Skipping in DMD: What is it and whom can it help?, Quest, October-December 2011.)

A phase 2 trial of GSK2402968 in boys with DMD who are still walking opened in Cincinnati in November 2011 and will open at 13 other U.S. sites, probably by early 2012. Participants must have mutations whose effects can be counteracted by skipping exon 51 of the dystrophin gene; be at least 5 years old; have been taking corticosteroids for a minimum of six months prior to screening; and meet other study criteria.

Contact the U.S. GSK Trials Call Center at (877) 379-3718 or For details, enter NCT01462292 in the search box at

A trial of GSK2402968 in nonwalking boys with DMD who meet study criteria is likely to open at one or more U.S. centers in mid-2012. Details will be posted on

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AVI BioPharma to develop drugs targeting exons 45, 50

AVI BioPharma, a Bothell, Wash., biopharmaceutical company, announced Nov. 15, 2011, that it will expand its development of exon-skipping drugs to treat Duchenne muscular dystrophy (DMD) in people with specific mutations in the dystrophin gene.

The company said it will enter into collaborations with Children’s National Medical Center in Washington, D.C., Carolinas Medical Center in Charlotte, N.C., and the U.S. National Institutes of Health (NIH) to develop two new exon-skipping compounds — one to encourage cells to skip exon 45 and the other to skip exon 50 of the dystrophin gene.

AVI currently is testing its experimental drug eteplirsen, designed to cause skipping of exon 51 of the dystrophin gene. A phase 2 trial of eteplirsen in DMD is ongoing at Nationwide Children’s Hospital in Columbus, Ohio, with supplemental support from MDA. This trial is no longer recruiting participants.

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CoQ10, lisinopril being studied in DMD, BMD, some LGMD subtypes

Researchers at five U.S. centers and one Canadian center are conducting a clinical trial of coenzyme Q10 and lisinopril to determine their possible beneficial effects on heart function in Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD) and five forms of limb-girdle muscular dystrophy (LGMD) — LGMD2C, LGMD2D, LGMD2E, LGMD2F or LGMD2I.

The trial is under the auspices of the Cooperative International Neuromuscular Research Group (CINRG) and has funding from the U.S. Department of Defense.

Coenzyme Q10 (coQ10) is involved in energy production in cells and is also an antioxidant, meaning it combats a form of cell damage called oxidative stress. It’s considered a dietary supplement and is available without a prescription.

Lisinopril (brand names Prinivil, Zestril) is a prescription drug that reduces stress on the cardiovascular system. It belongs to a class of drugs known as angiotensin converting enzyme (ACE) inhibitors.

The study will include 120 participants who are at least 8 years old. They will be randomly assigned to receive either coenzyme Q10 alone, lisinopril alone, a combination of coenzyme Q10 and lisinopril, or no study medication.

Prospective participants must have a confirmed genetic diagnosis of DMD, BMD or LGMD2C, LGMD2D, LGMD2E, LGMD2F or LGMD2I; have no clinical cardiac symptoms; have never taken cardiac medications known as beta blockers; have not taken coenzyme Q10 or an ACE inhibitor at any time for more than six months; or at all in the three months prior to study enrollment; and meet other study criteria.

U.S. study sites are in Washington, D.C.; Chicago; St. Louis; Charlotte, N.C.; and Pittsburgh. The Canadian site is in Calgary, Alberta.

Send email to; or contact Lauren Hache in the Seattle area at (206) 451-4496 or For details, enter NCT01126697 in the search box at

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BioMarin plans to seek U.S. approval of LEMS drug

BioMarin Pharmaceutical of Novato, Calif., is conducting a multicenter study of 3,4-diaminopyridine phosphate (3,4-DAP), also known as amifampridine phosphate, in adults with Lambert-Eaton myasthenic syndrome (LEMS).

In December 2009, BioMarin received approval to market 3,4-DAP as Firdapse for LEMS in the European Union. The company is planning to seek approval from the U.S. Food and Drug Administration (FDA) to market the drug for LEMS in the United States.

3,4-DAP increases the release of acetylcholine, a chemical transmitter of signals from the nervous system that activate muscle fibers.

LEMS is caused by a misdirected attack of the immune system on nerve endings at the neuromuscular junction, the place where nerve and muscle fibers connect. The disorder causes weakness and sometimes other symptoms, such as dry mouth or constipation. In the United States, the disease is treated with medications that suppress the immune system and/or medications that slow the breakdown of acetylcholine.

Participants must be at least 18 years old; have normal respiratory and swallowing function and a normal electrocardiogram (EKG); and meet other study criteria.

U.S. sites are in Birmingham, Ala.; Scottsdale, Ariz.; Little Rock, Ark.; Orange, Calif.; Jacksonville, Fla.; Kansas City, Kan.; New York; and Philadelphia.

Contact Kenny Jones at BioMarin in California at or (415) 506-6700. For details, go to, and enter NCT01377922 in the search box.

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Team receives prestigious prize for MDA-supported LGMD work

Jerry Mendell, neurologist, MDA research grantee
Jerry Mendell is a neurologist and MDA research grantee at Nationwide Children’s Hospital in Columbus, Ohio, where he directs the Center for Gene Therapy and the MDA clinic.

A team headed by neurologist Jerry Mendell, a longtime MDA research grantee and director of the MDA Clinic at Nationwide Children’s Hospital in Columbus, Ohio, has received the prestigious Annals of Neurology prize for an outstanding contribution to clinical neuroscience.

The award was based on Mendell’s and colleagues’ MDA-supported research on transfer of alpha-sarcoglycan genes to treat type 2D limb-girdle muscular dystrophy (LGMD2D).

In this study, two out of three trial participants with LGMD2D showed sustained alpha-sarcoglycan protein production from the transferred genes six months after the genes were injected into a foot muscle.

One person showed evidence of an unwanted immune response against the viral vehicle used to deliver the genes. (See Researchers encouraged by LGMD gene therapy trial results, Clinical Trials and Studies Winter 2011, Quest, January-March 2011.)

MDA is currently supporting the next phase of that research. Mendell will co-chair an MDA-sponsored conference in March 2012 on current best practices and development of new therapies for neuromuscular disorders.

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Cytokinetics testing CK-2017357 in MG

The South San Francisco, Calif., pharmaceutical company Cytokinetics, in conjunction with the National Institute of Neurological Disorders and Stroke (NINDS), is testing its experimental compound CK-2017357 against a placebo in a phase 2, multicenter trial slated to include 36 adults with myasthenia gravis (MG).

Participants must have evidence of muscle weakness; antibodies (immune system proteins) to the acetylcholine receptor, the part of the muscle fiber that receives signals from the nervous system; and meet other study criteria.

CK-2017357 is designed to increase the sensitivity of skeletal muscle fibers to calcium, possibly increasing muscle force and prolonging the time it takes for muscles to fatigue. The investigators will be evaluating the effect of CK-2017357 on muscle strength, muscle fatigue and pulmonary function.

There are 16 study sites distributed across the United States. Contact Jean Masonek at Cytokinetics in South San Francisco at or (650) 624-2929; email is preferred. For details, go to, and enter NCT01268280 in the search box.

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Thymectomy in MG being studied

The National Institute of Neurological Disorders and Stroke is funding a phase 3 trial of a surgical procedure known as thymectomy — removal of the thymus — in about 150 adults with myasthenia gravis (MG) at 50 sites throughout the United States and other countries.

Removal of the thymus, an organ located in the chest that plays a role in the immune system, has been used for many years as a treatment for MG, an autoimmune disease. However, conclusive data on its effectiveness are lacking.

This study seeks to gather data on whether thymectomy plus the steroid drug prednisone is more effective than prednisone alone, and whether the amount of prednisone required to control symptoms differs when a thymectomy has been performed.

Participants must be 18 to 65 years old; meet diagnostic criteria for MG; have experienced onset of generalized MG within the last five years; not have a tumor in the thymus (thymoma); and meet other study criteria.

Study participants will be randomly assigned to receive treatment with prednisone alone or to receive prednisone plus a thymectomy. They’ll be followed for at least three years.

Call Gary Cutter, Greg Minisman or ChiChi Aban at the University of Alabama at Birmingham Biostatistics Department at (205) 934-4905; or Gary Cutter at (205) 975-5048. For details, enter NCT00294658 into the search box at

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Periodic paralysis mouse model developed

MDA grantee Stephen Cannon at the University of Texas Southwestern Medical Center in Dallas coordinated a study team that has developed a mouse model of one type of hypokalemic periodic paralysis, publishing the development in the Oct. 3, 2011, issue of the Journal of Clinical Investigation.

Hypokalemic periodic paralysis, a genetic muscle disorder involving attacks of weakness or paralysis associated with low serum potassium levels, can be caused by any of several different mutations in the genes encoding a muscle calcium channel or sodium channel. The newly developed mouse model has a mutation in the muscle sodium channel.

The mouse model will enable researchers to study the sodium-channel form of hypokalemic periodic paralysis in more depth and test potential treatments.

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BioMarin testing BMN701 in late-onset Pompe disease

BioMarin Pharmaceutical is seeking participants for a trial testing the safety and tolerability of its experimental drug BMN701 in adolescents and adults with late-onset Pompe disease (acid maltase deficiency).

BMN701 is an enzyme replacement therapy, or ERT. The laboratory-engineered compound is designed to replace the enzyme acid maltase — also known as acid alpha glucosidase, or GAA — which is deficient in Pompe disease. Its formulation differs from that of Myozyme or Lumizyme, currently available ERTs for Pompe disease.

This phase 1-2 trial is open-label, meaning there is no placebo group. All participants will receive BMN701 by intravenous infusion every two weeks over an approximately six-month period.

Participants must be at least 13 years old; have not previously received ERT; be able to walk at least 131 feet (assistive devices permitted); and meet other study criteria.

Study sites are in Los Angeles; San Diego; Gainesville, Fla.; and Kansas City, Kan. Contact Sean McCarthy at BioMarin in Novato, Calif., at For details, go to, and enter NCT01230801 in the search box.

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Systemic antisense injections rescue SMA mice

Adrian Krainer, MDA grantee
Adrian Krainer, an MDA grantee at Cold Spring Harbor (N.Y.) Laboratory, coordinated a research group that found that antisense treatment in SMA mice is most effective when it reaches all body tissues.

Treatment of a mouse model of severe spinal muscular atrophy (SMA) with an antisense oligonucleotide results in greater and longer-lasting benefit when given systemically than when given only to the central nervous system, recent research shows.

The findings imply that strategies to increase levels of functional SMN protein, which is deficient in SMA, have more benefit if given in a way that reaches the entire body (systemically) as opposed to just the brain and spinal fluid; and that SMA is a disease not only of the central nervous system but of other tissues, such as the liver and muscles.

Systemic delivery of the antisense compound ASO-10-27 resulted in a median survival time for treated mice in the highest dosage group that was about 25 times the median survival time for untreated animals (248 days compared to 10 days).

By contrast, when the drug was delivered only to the central nervous system, the median survival time was only 1.6 times that of untreated animals (16 days compared to 10 days).

Scientists at Cold Spring Harbor Laboratory (N.Y.) and Isis Pharmaceuticals in Carlsbad, Calif., supported in part by MDA, reported the findings Oct. 6, 2011, in the journal Nature. MDA research grantee Adrian Krainer, a professor at Cold Spring Harbor Laboratory, coordinated the study team.

Antisense oligonucleotides are synthetic molecules that can change the final genetic instructions for proteins. In SMA, antisense oligonucleotides can change the way cells process the genetic instructions (RNA) from a gene called SMN2 so that more full-length, functional SMN protein can be made from this gene. (Most of the protein made from the SMN2 gene is short and not functional.)

The dosage and timing of the ASO therapy also was important. In general, higher doses and earlier treatment were better than lower doses and later treatment. Most of the mice that received subcutaneous (under the skin) doses of the ASO within the first few days of life, with or without brain injections of the ASO, showed no overt signs of motor dysfunction.

“It remains to be seen to what extent some of these findings in mice will hold for SMA patients,” Krainer said.

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About Clinical Trials

About Clinical Trials

A clinical trial is a test, in humans, of an experimental treatment. Although it's possible that benefit may be derived from participating in a clinical trial, it's also possible that no benefit, or even harm, may occur.

MDA has no ability to influence who is chosen to participate in a clinical trial.

To learn more, see Understanding Clinical Trials and Being a Co-Adventurer, which is about neuromuscular disease clinical trials. To see a continuously updated database of clinical trials, go to

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