AAN Research Briefs on DM, DMD, LGMD, MG, MMD, SMA

Reports from the American Academy of Neurology annual meeting about Duchenne, limb-girdle and myotonic muscular dystrophies, dermatomyositis, myasthenia gravis and spinal muscular atrophy

Article Highlights:

This article contains brief reports on research presented at the 63rd annual meeting of the American Academy of Neurology (AAN), held in Honolulu April 9-16, 2011:

  • Etanercept in dermatomyositis
  • AVI-4658 in Duchenne MD (DMD)
  • PRO051/GSK2402968 in DMD
  • Gene therapy in type 2C limb-girdle MD
  • Regulatory T cells in myasthenia gravis
  • RNA interference in type 1 myotonic dystrophy
  • Motor neurons from skin cells in spinal muscular atrophy (SMA)
  • Neuromuscular junction effects in SMA
  • Valproic acid and carnitine in SMA
by Margaret Wahl on April 20, 2011 - 4:49pm

Below are brief reports and links to more information about neuromuscular disease research presented at the 63rd annual meeting of the American Academy of Neurology (AAN), held in Honolulu April 9-16, 2011.

Adding etanercept allowed dermatomyositis patients to take less prednisone

Favorable results were reported from a pilot study of etanercept (Enbrel) in dermatomyositis (DM). Results, reported April 13, indicated etanercept was safe and well tolerated and allowed trial participants who received it to take less of the corticosteroid drug prednisone in order to control disease symptoms.

Eleven participants began the trial on prednisone plus etanercept, and five started on prednisone plus a placebo. After week 24, the median prednisone dose in the placebo group needed to control the disease was 29.2 milligrams per day, while in the etanercept group it was 1.2 milligrams per day.

Five participants who received etanercept developed worsening rash during the study compared to one participant who was taking the placebo.

Like prednisone, etanercept is an immunosuppressant and anti-inflammatory medication. Its mechanism of action, however, is different from that of prednisone. Etanercept is marketed under the brand name Enbrel for treatment of certain types of arthritis, the joint disease ankylosing spondylitis, and the skin disease plaque psoriasis.

Because chronic treatment with corticosteroids can result in significant side effects such as weight gain, bone loss and psychological distress, finding a drug that lowers the need for corticosteroids can be beneficial.

However, etanercept also has a down side, including increasing the risk of developing serious infections and possibly increasing the risk of certain malignancies and autoimmune (self-immune) disorders.


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Exon skipping drug AVI-4658 (eteplirsen) results in dystrophin production in Duchenne MD trial

Francesco Muntoni from UCL Institute of Child Health in London presented complete results of a 26-week study by AVI BioPharma of the company's experimental exon skipping drug.

The drug — previously called AVI-4658 but recently renamed eteplirsen — was delivered intravenously to children with Duchenne muscular dystrophy (DMD).

The complete results, reported April 13, confirmed earlier analysis that participants tolerated all doses well, and new expression (production) of dystrophin was seen. Dystrophin is the muscle protein missing in DMD.

Results of this phase 1b-2 trial were originally announced in October 2010 at the World Muscle Society meeting in Japan. (See Intravenous AVI4658 Shows Safety, Benefit in DMD.)

The study, conducted in the United Kingdom, included 19 boys ages 5-15 with DMD who have mutations in the dystrophin gene that can potentially benefit from skipping of exon 51, the target effect of eteplirsen.

Skipping an exon (region) of a gene is a strategy designed to cause cells to assemble genetic instructions differently and produce a functional protein despite the presence of a genetic mutation.

Muscle biopsies were performed at baseline and at 14 weeks, and the patients were followed for a total of 26 weeks.

All 19 participants tolerated all doses well. Dystrophin production and restoration of dystrophin-associated proteins at the muscle-fiber membrane were seen. Indications of reduced inflammation also were noted.

The maximum dystrophin levels were 18 percent of normal, and the maximum percentage of dystrophin-positive fibers seen on a biopsy was 55 percent.

The investigators said functional benefit will be assessed in future studies that employ higher doses of eteplirsen for longer periods of time.

Screening is under way for a U.S. trial of eteplirsen (AVI-4658) in Columbus, Ohio. Contact Ana Maria Gomez at Nationwide Children's Hospital at (614) 722-2715 or anamaria.gomez@nationwidechildrens.org.

For more, see:

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PRO051/GSK2402968 exon skipping drug for DMD results in dystrophin production, increased walking distance

Favorable results also were reported for a phase 1-2 trial of another experimental drug that skips exon 51 in the dystrophin gene.

The drug, PRO051/GSK2402968, is in development by Prosensa and GlaxoSmithKline, and is designed to treat patients with Duchenne muscular dystrophy (DMD) with certain dystrophin mutations.

(Note: The experimental exon skipping drug eteplirsen, reported on above, has the same target as PRO051/GSK2402968, but the drugs are different molecules.)

Results presented April 13 of the 48-week trial of PRO051/GSK2402968 showed increased presence of the muscle protein dystrophin in muscle fibers; and an increase over baseline measurements of the distance participants could walk in six minutes.

No serious adverse events or unwanted immune responses were noted, although some participants had low-level excretion of protein in the urine, a possible sign that the kidneys were being damaged.

The 12 boys who participated in this 48-week study, conducted in Belgium and Sweden, all had DMD caused by dystrophin gene mutations that potentially are treatable by skipping exon 51.

The boys initially were given weekly subcutaneous (under the skin) injections of PRO051/GSK2402968 at variable and increasing dosage levels for five weeks.

After this dose escalation period, they all received the highest dose — 6 milligrams per kilogram of body weight per week — for an additional 12 weeks.

Results of this first 17-week period were published in March; the April 13 presentation at the AAN meeting included results from an additional 31 weeks of the study.

Results of the first 17 weeks of this trial showed no serious adverse events occurred, and no unwanted immune responses to the treatment were detected. The distance the children were able to walk in six minutes increased an average of 35.2 meters (about 116 feet) compared to baseline measurements.

Investigators at that time noted some increased excretion of protein in the urine.

After the additional 31 weeks of treatment at the 6-milligram-per-kilogram weekly dose, the investigators continued to report no serious adverse events, and the increase in the distance walked in six minutes was maintained.

Dystrophin protein was seen in 100 percent of the muscle fibers in some of the muscle biopsy samples.

However, the investigators did continue to see low-level urinary excretion of protein, which they say warrants further monitoring.

A phase 1 study of PRO051/GSK2402968 is under way and recruiting in Ohio. This study is for boys with DMD who are no longer walking and have dystrophin mutations that could be helped by skipping exon 51. See:

Phase 2 and phase 3 studies of PRO051/GSK2402968 in DMD are being conducted outside the United States. See:

For the 17-week trial results published in March 2011, see:

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Moderately encouraging results seen with injections of gamma-sarcoglycan gene in type 2C LGMD

An investigator from a French and Tunisian research team presented moderately encouraging results on April 13 from a phase 1 (safety and tolerability) trial of intramuscular gene therapy for the type 2C form of limb-girdle muscular dystrophy (LGMD).

Trial results found that participants who received mid-to-high dosages of gamma-sarcoglycan genes showed evidence of gamma-sarcoglycan protein production. LGMD2C is caused by a deficiency of the gamma-sarcoglycan protein at the muscle-fiber membrane, as a result of mutated gamma-sarcoglycan genes.

In this study, nine participants ages 16 to 38 were divided into three dosage groups. The first two groups received a single injection into a forearm muscle of gamma-sarcoglycan genes encased in AAV1 viral shells.

The second group received a higher dose than the first group; the third group received three injections at the same site, for the highest total dose.

The therapy was well tolerated, and those in the mid-to-high dosage ranges showed evidence of gamma-sarcoglycan protein production from the injected genes. One trial participant had an immune response either to the AAV1 shell or to the gamma-sarcoglycan protein.

The investigators interpreted their results as basically positive and as paving the way for future developments in gene therapy for muscle diseases.

Editor's note 1/19/12: A scientific paper with full results on the LGMD2C gene therapy study was published online in the journal Brain on Jan. 11, 2012. For a summary, see

A phase I trial of adeno-associated virus serotype 1-gamma-sarcoglycan gene therpay for limb girdle muscular dystrophy type 2C.

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Regulatory T cells aren't up to par in people with MG

Matthew Meriggioli, an MDA research grantee at the University of Illinois-Chicago, presented his group's findings on abnormalities of regulatory T cells in people with myasthenia gravis (MG).

MG is a disease in which the immune system mistakenly attacks the neuromuscular junctions, where nerve and muscle fibers meet. Effector T cells produced by the immune system enhance the immune response, while regulatory T cells dampen it.

Meriggioli's research group studied 12 people with MG and 11 without the disease, and found that those with MG had regulatory T cells that were defective in their ability to dampen an immune response, as compared to regulatory T cells from people without MG.

This was true whether or not MG was well controlled in the participant, and with or without drugs to suppress the immune system.

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Investigators somewhat encouraged by RNA interference in mouse model of MMD1 (DM1)

Joel Chamberlain from the University of Washington-Seattle presented moderately encouraging results from her group's experiments using a strategy called RNA interference in a mouse model of type 1 myotonic dystrophy (MMD, or DM).

The investigators found the experimental compounds entered muscles well after systemic injection and, in some of the mice, favorable effects were seen on a process called splicing in a gene known as SERCA1.

RNA interference is one of several strategies in development designed to block unwanted genetic instructions (RNA). Blocking the extra RNA that's erroneously produced in type 1 and type 2 MMD could eventually become a treatment for these diseases.

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Motor neurons can be made from human skin cells, with implications for SMA

Stefania Corti from the University of Milan (Italy) presented her group's findings April 14, showing that motor neurons can be generated, without using viruses, from human skin cells and that these cells may have research and therapeutic implications for spinal muscular atrophy (SMA).

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 then to become motor neurons, the cells affected in SMA. 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 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 the father.

The investigators said the results show it may be possible to generate stem cells from specific SMA patients and that these might have value for both SMA research and therapy.

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Nerve-muscle junctions are affected early in SMA mouse; trichostatin helpful

On April 14, a member of the laboratory of MDA research grantee Chien-Ping Ko at the University of Southern California in Los Angeles reported that there was a major drop in the number of intact neuromuscular junctions in a mouse model of SMA very early in life and that this effect could be ameliorated by treating the mice with the drug trichostatin (TSA).

Neuromuscular junctions are the places where nerve fibers meet muscle fibers.

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Valproic acid plus carnitine not helpful in SMA; associated with weight gain

John Kissel from Ohio State University presented negative results on April 13 for part 2 of a trial of valproic acid and carnitine in children and adolescents with spinal muscular atrophy (SMA).

Part 2 results showed no difference in motor function in treated participants. Investigators have concluded that valproic acid and carnitine are not beneficial in children with spinal muscular atrophy and could be considered harmful due to the common side effect of excessive weight gain.

Unfavorable results for part 1 of this trial were announced in 2010 (see Research Briefs: ALS, CMD, FA and SMA).

Part 1 studied 61 children with SMA ages 2 to 8 who were unable to walk or stand. Participants were randomly assigned to receive valproic acid and carnitine, or placebo treatment for six months, with all participants receiving the active drugs for the following six months.

At six months in part 1 of the trial, there was no difference in function (measured by the Hammersmith Functional Motor Scale score) between the treatment and placebo groups; and excessive weight gain was the most frequent drug-related adverse event.

Part 2 of this trial included 28 children with SMA who were ages 3 to 17 and able to walk or stand.

Again, there were no significant changes in any primary outcome measure at six or 12 months, and the most common adverse event was weight gain, seen in 85 percent of the participants.

Over a one-year period, 20 percent of participants gained more than 20 percent of their weight compared to the starting point, which was considered detrimental to function in these SMA-affected children.

Editor's note 5/5/11: This story was updated to reflect new information received from an investigator on the etanercept in dermatomyositis study.


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