Research Updates Winter 2010

Article Highlights:

The latest news on research as of December 2009:

by Quest Staff on December 31, 2009 - 1:17am

QUEST Vol. 17, No. 1

Featured in this issue: Duchenne and Becker MD ** Facioscapulohumeral MD ** Friedreich's ataxia ** Limb-Girdle muscular dystrophy ** Myotonic dystrophy ** Spinal muscular atrophy

Exon skipping strategy for DMD makes strides

A strategy in which muscle cells are coaxed to ignore error-containing sections (“exons”) of the dystrophin gene has shown promise in dogs and mice with a disease resembling Duchenne muscular dystrophy (DMD) and is moving ahead in human testing. MDA has been funding laboratory development of “exon skipping” for about a decade, and the biotechnology companies now developing the strategy for human use have relied on this research.

An exon skipping compound called PRO051, developed by Prosensa (, a biotech company in Leiden, Netherlands, was found in 2007 to allow dystrophin protein production in four boys with DMD.

In October 2009, the multinational pharmaceutical company GlaxoSmithKline ( announced it will now develop and commercialize PRO051 for people with DMD who may benefit from skipping exon 51 of the dystrophin gene.

At the same time that Prosensa was developing PRO051 in the Netherlands, AVI BioPharma ( of Bothell, Wash., was developing AVI4658, which also takes aim at exon 51. In January 2009, the company announced that injecting this compound into the muscle fibers of boys with DMD caused dystrophin to be made. The compound is now undergoing further testing in the United Kingdom, and, in November 2009, AVI announced it would soon begin testing the drug in the United States. That testing is slated to begin this year at Nationwide Children’s Hospital in Columbus, Ohio, which is a part of MDA’s DMD Clinical Research Network. (See “First U.S. exon skipping trial”.)

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Stop codon read-through for DMD moving forward

Another gene-modifying strategy directed at DMD, and one which has also received MDA support, is “stop codon read-through.” This strategy, also called “nonsense mutation read-through,” targets mutations in the dystrophin gene that prematurely stop the synthesis of the dystrophin protein. The strategy causes muscle cells to ignore these mutations and synthesize dystrophin.

MDA has funded development of the stop codon read-through technique via PTC Therapeutics ( of South Plainfield, N.J. Results are expected by 2011 of a phase 2 trial of PTC’s stop codon read-through drug Ataluren (formerly called PTC124) in about 175 ambulatory (able to walk 80 yards) boys with DMD.

As of late 2009, a study of Ataluren in nonambulatory boys was getting under way.

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DMD gene therapy update

Since the late 1980s, MDA has spent several million dollars to identify, understand and miniaturize the dystrophin gene, which is mutated in DMD and the related disease, Becker muscular dystrophy (BMD).

These efforts culminated in a recent MDA-supported study in which the gene for dystrophin was injected into a biceps muscle in six boys with DMD. The trial participants each received an injection of Biostrophin, a patented compound containing a miniaturized dystrophin gene and viral delivery vehicle, developed by the MDA-supported biotech company Asklepios (, located in Chapel Hill, N.C.

Investigators have announced that the procedure was well tolerated at two dosage levels. MDA and its advisors are evaluating the data in detail prior to deciding on next steps.

The headline on this article was changed on 1-15-10 to correct the misimpression that Asklepios’ gene therapy research is on hold. The company is moving forward with studies required for whole-limb delivery of Biostrophin.

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MDA backs development of anti-inflammatory drugs

Catabasis Pharmaceuticals (, of Cambridge, Mass., has received a grant from MDA, through its drug development program, to identify and test small molecules that interfere with inflammation in mouse models of DMD, with the goal of moving into human testing late in 2010. Inflammation is thought to play a role in hastening muscle destruction in DMD.

Validus Biopharma, of Rockville, Md., has received a similar MDA grant, to develop “nonhormonal steroid” drugs for DMD that can inhibit an inflammatory pathway controlled by a natural compound called NF-kappa B. Corticosteroid drugs, such as prednisone and deflazacort, are known to inhibit inflammation via NF-kappa B interference, but their side effects are a limiting factor in their usage. Validus hopes to have a compound to test in human trials in DMD by 2012.

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New research has shown that variations in a gene not previously connected to type 2C limb-girdle muscular dystrophy (LGMD2C) can increase or decrease the severity of the disease in mice and are likely to do the same in people with this and perhaps with related types of muscular dystrophy.

The gene, called LTBP4, influences two processes: muscle-tissue scarring, and fragility of the membrane that surrounds each muscle fiber, reports study coordinator Elizabeth McNaly, who has MDA funding for related work at the University of Chicago.

McNaly’s team found that the course of the disease was made milder by unique changes in the LTBP4 gene.

The researchers, who published their findings online Nov. 2, 2009, in the Journal of Clinical Investigation, have speculated that modifying the actions of the LTBP4 gene or protein could also have implications for other muscular dystrophies, such as types 2D, 2E and 2F LGMD, and Duchenne and Becker muscular dystrophies.

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Pentamidine ID’d as potential starting point for MMD1 drug

A drug called pentamidine, which is approved by the U.S. Food and Drug Administration (FDA) to treat a type of pneumonia, some yeast infections, and the parasitic diseases leishmaniasis and sleeping sickness, also has the potential to be modified and developed into a treatment for type 1 myotonic dystrophy (MMD1, also known as DM1).

MDA grantee Andrew Berglund at the University of Oregon was on the research team that published the pentamidine study results online Oct. 12, 2009, in Proceedings of the National Academy of Sciences.

In experiments in mice with an MMD1-like disease, pentamidine injections interfered with a toxic interaction that occurs at the molecular level in both rodents and humans. It inhibited interaction between a protein called MBNL and “CUG repeats,” which are abnormally expanded genetic instructions associated with MMD1.

Berglund said pentamidine in its present form is too toxic to be used for this purpose, which would require high doses. However, he noted that the pentamidine molecule has the potential to be modified for use in treating MMD1.

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DUX4 gene fingered as possible culprit

Abnormal activity of a gene called DUX4, located on chromosome 4 near the DNA deletion that’s known to cause facioscapulohumeral muscular dystrophy (FSHD), may play a larger role in this disease than previously thought, according to an MDA-supported scientific team.

The researchers, who published their findings in the July 2009 issue of Human Molecular Genetics, found that pieces of the DUX4 gene, which is for the most part inactive, are abnormally activated in FSHD-affected cells. At least one of the protein molecules made from the partially activated DUX4 gene sections was found to interfere with muscle development in cells in the lab, and others could also have toxic effects, the researchers say.

FSHD results from a mutation that removes a small stretch of DNA from chromosome 4, although the precise effects of this “deletion” are unclear. If the DUX4 findings are confirmed, blocking its activation or the protein products made from it, could become an avenue for FSHD therapy development.

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SMN production increased with tetracycline-like drug

In spinal muscular atrophy (SMA), therapeutic efforts largely have been directed toward changing the instructions (code) contained in a gene called SMN2, in hopes of producing more full-length SMN protein, the protein that’s deficient in this disease.

In November 2009, scientists announced that an experimental compound called PTK-SMA1, developed by Paratek Pharmaceuticals ( of Boston, and other institutions, significantly increased the amount of full-length SMN protein in mice. However, it was unable in its present form to penetrate the central nervous system, which it would have to do to reach the motor neurons, the muscle-controlling nerve cells in the spinal cord that are the primary cells affected in SMA. The drug is a chemical cousin of the antibiotic tetracycline.

Adrian Krainer, an author on the PTK-SMA1 study published online in Science Translational Medicine Nov. 4, 2009, has received MDA funding for related work in SMA.

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Gene variant ID’d that lessens severity of disease in SMA

In August 2009, scientists identified a variant in the SMN2 gene that leads to production of more of the needed full-length SMN protein and lessens the severity of the disease course in SMA. The finding could lead to therapeutic strategies and will almost certainly lead to better prediction of disease course.

The study team, which included several former and current MDA grantees, published results online Aug. 27, 2009, in the American Journal of Human Genetics.

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Repligen compound hits its target

In November 2009, MDA, through its Venture Philanthropy drug development program, awarded a new grant to the Repligen Corp. ( in Waltham, Mass., to develop a specific molecule that increases production of the needed frataxin protein in mice with a disease resembling human Friedreich’s ataxia (FA). (Repligen received MDA funding from 2007 through November 2009 for earlier-stage development of FA treatments. And Joel Gottesfeld, a scientist at the Scripps Institute in La Jolla, Calif., in whose lab the Repligen compound originally was developed, received MDA funding in 2004 and 2005.)

In September 2009, scientists announced the experimental drug they’re working with specifically targets an enzyme called histone deacetylase (HDAC) 3. In mice, blocking this enzyme allows cells to produce the needed frataxin protein despite the presence of a genetic mutation in the frataxin gene, the underlying cause of FA. (See “Epigenetics: Above and Beyond Genes.”)

Gottesfeld published the new findings Sept. 25, 2009, in the journal Chemistry & Biology, with colleagues Chunpung Xu at Scripps, MDA grantee James Rusche at Repligen, and others.

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Editor’s note: Why wait? New research updates are posted frequently on MDA’s Web site. Sign up at Quest’s online site to be notified when a Quest News story is posted, or to receive monthly summaries.

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