This article includes items about research in: Duchenne MD, limb-girdle MD, inclusion-body myositis, polymyositis, dermatomyositis, FSH dystrophy, myotonic muscular dystrophy and researcher George Karpati.
MDA has joined with three other organizations to form the Duchenne Research Collaborative International (DRCI). At a January meeting in Paris, the Association Francaise Contre les Myopathies (AFM) of France, the United Parent Project Muscular Dystrophy (UPPMD) of the Netherlands, the United Parent Project Muscular Dystrophy of the United States and MDA signed a “memorandum of understanding” that they’ll cooperate, collaborate and communicate openly to support promising research.
DRCI leaders plan to establish a clearinghouse for research investments and resources on Duchenne muscular dystrophy (DMD), which will allow DMD researchers to track research grants and locate key resources. The new cooperative also will start a global patient registry, consolidating regional registries into a large database through which investigators can study a larger population and locate clinical trial candidates. DRCI will also create a global clinical trial network.
“This is a monumental day for the entire Duchenne muscular dystrophy community throughout the world,” said Louis Kunkel, professor of genetics and pediatrics at Harvard Medical School in Boston and head of the team that in 1986 identified the dystrophin gene, which underlies DMD when flawed.
“This historic collaboration among the leading DMD organizations in the world has the potential to provide a real and major boost to the efforts against this devastating and deadly disease.”
When MDA grantee Giulio Cossu at the Stem Cell Research Institute of the San Raffaele Scientific Institute of Milan (Italy), and colleagues, tested the experimental drug HCT 1026 in mouse models of Duchenne muscular dystrophy (DMD) and type 2D limb-girdle MD (LGMD2D), they found it was more effective than a corticosteroid drug in the prednisone family, and that it didn’t have the side effects of corticosteroids.
HCT 1026 is derived from flurbiprofen (Ansaid), an anti-inflammatory drug approved by the U.S. Food and Drug Administration for the treatment of arthritis. Besides easing the pain of inflammation, HCT 1026 also releases nitric oxide, which has been shown to have beneficial effects on muscle repair and regeneration.
The researchers, who published their findings in the Jan. 2 issue of Proceedings of the National Academy of Sciences, tested the compound in mice with diseases resembling DMD and LGMD2D.
In both instances, HCT 1026 maintained muscle structure and function, and reduced inflammation. The mice gained strength and performed better on tests of movement. HCT 1026 was “significantly more potent” than the corticosteroid prednisolone, with no detectable side effects. (In humans, side effects of corticosteroids, such as weight gain, can be problematic.)
The investigators say that, when they combined the drug treatment with injections of mesoangioblast stem cells into an artery, they saw better integration of the stem cells into muscle, more improvement of muscle tissue structure and better treadmill performance than they saw with stem cells alone.
Mesoangioblasts were identified by Cossu’s team and have shown promise in treating dystrophin-deficient dogs (see Scientists Bullish on Stem Cells for Muscle Repair, January-February).
Recent findings by researchers at Harvard Medical School, Brigham and Wo-men’s Hospital, and Children’s Hospital, all in Boston, have identified a type of immune system cell previously undetected in the biopsy samples of people with inclusion-body myositis (IBM).
MDA grantee Steven A. Greenberg at Harvard and Brigham and Women’s, and colleagues, who published their findings in the January issue of Muscle & Nerve, say the results suggest new hypotheses about IBM, as well as new potential treatment possibilities.
The cells, called dendritic cells, haven’t been previously reported in IBM muscle samples, because their identification requires looking at muscle specimens using specific markers, Greenberg says. Previous studies have used a more general type of marker and have misidentified many of the dendritic cells as T-cells, a better known immune system cell.
“Until the last decade, the study of dendritic cells has been relatively neglected in immunology and particularly in autoimmune disease,” Greenberg says, referring to diseases in which the body’s immune system mistakenly attacks its own tissue. Polymyositis (PM) and dermatomyositis (DM), in which dendritic cells have previously been noted, have long been classified as autoimmune disorders. Experts have disagreed about how to classify IBM, although most believe the immune system is involved in some way.
“These [dendritic] cells are now recognized as central to the initiation and development of specific immune responses,” Greenberg says. One type, myeloid dendritic cells, is particularly abundant in IBM muscle tissue.
“Myeloid dendritic cells activate other immune system cells, particularly T-cells that are believed to be a major cause of muscle damage in IBM and polymyositis. Their presence in IBM and PM muscle provides a means by which these T-cells become activated and attack muscle.”
Greenberg says new therapies for autoimmune diseases aimed at disrupting the function of dendritic cells and their interaction with T-cells could be considered for future trials in myositis, given these findings. He notes that two drugs — abatacept (Orencia) and efalizumab (Raptiva), both of which interfere with dendritic cell-T-cell interactions — are already approved by the Food and Drug Administration for other conditions.
Researchers at Leiden University in the Netherlands have added to existing knowledge about the FRG1 protein, which is made from a gene strongly implicated in facioscapulohumeral MD (FSHD) by some prominent investigators.
Silvana van Koningsbruggen and colleagues, including MDA-funded Silvere van der Maarel, say their experiments demonstrate the probable role of FRG1 in RNA splicing, a cellular process that takes “rough draft” genetic instructions to their final version.
Their paper, published online Nov. 14 in Chromosoma, reports identification of several splicing-related proteins associated with FRG1.
A research group that included Charles Thornton and Rabi Tawil, MDA clinic co-directors at the University of Rochester (N.Y.) Medical Center, have found evidence that blood vessel abnormalities may be involved in facioscapulohumeral muscular dystrophy (FSHD).
When they analyzed gene activity in people with FSHD, myotonic dystrophy (MMD) and no muscular dystrophy, they found that 44 genes were specifically overactive (upregulated) in early FSHD, and that 11 of these (32 percent) had a role in blood vessel structure or function.
<>These findings may help explain why retinal blood vessel abnormalities sometimes are part of FSHD. The researchers, who published their findings online Dec. 6 in Neurology, speculate that blood flow irregularities inside muscle fibers could also be a contributing factor in FSHD.
Late last year, George Karpati, a world-renowned neuromuscular disease specialist and a longtime MDA grantee at the Montreal Neurological Institute (MNI), received the Prix du Quebec Wilder Penfield (Quebec Wilder Penfield Prize) and a special merit award from the Muscular Dystrophy Association of Canada. (Wilder Penfield, a pioneer in brain surgery who died in 1976, founded MNI in 1934.)
Karpati’s MDA-funded work has centered around strategies to transfer therapeutic cells and genes in Duchenne muscular dystrophy (DMD) and to increase production of the protein utrophin, which can partially compensate for the loss of the dystrophin protein that characterizes DMD.
He’s authored some 250 original research papers and articles and, since 2002, has edited or co-authored five major books on neuromuscular disease.
Karpati has received many additional accolades, including being knighted by the Ordre National du Quebec in 2005.