Vitamin C Aids
CMT1A Mice
High doses of ascorbic acid (vitamin C) can improve or stabilize
motor function in mice with a particular form of Charcot-Marie-Tooth
(CMT) disease, say researchers in France, who published their
results in the April issue of Nature Medicine.
Edith Passage and Jean Chretien Norreel at the Institute of Health
and Medical Research in Marseilles, and colleagues, gave high doses
of ascorbic acid to mice with CMT type 1A, a form of CMT that
results from abnormalities in the PMP22 protein (peripheral myelin
protein 22).
The human form of CMT1A usually results from a duplication in the
gene for PMP22 on chromosome 17, with consequent overproduction of
PMP22. It's this type of defect that the researchers reproduced in
the mice used in these experiments.
In addition to the improved function, they found evidence that the
ascorbic acid may have reduced PMP22 overproduction and thereby normalized
the formation of myelin, a sheath that surrounds nerve fibers and
helps signals move through the nervous system. The effect may be specific
to the type of CMT that results from PMP22 overproduction.
The investigators say they plan to begin clinical trials of vitamin
C in CMT1A in the near future, but they urge caution for the present.
Michel Fontes, who was on the study team, said, "We do not know if
ascorbic acid works in humans and what the optimal dose is." Fontes
went on to say that mice synthesize ascorbic acid, whereas humans
don't.
He also expressed concern that if enough patients begin taking large
doses of vitamin C on their own, it might be impossible to do a study
to find out whether it really works and what its toxicity might be.
Gene Found for CMT2A
A second gene that, when flawed, leads to CMT type 2A, has
been identified. A multinational research group that studied seven
families from varying ethnic backgrounds with this form of the disease
published its results online in Nature Genetics on April 4.
In type 2 forms of CMT, the primary problem is thought to be in the
nerve fiber itself, rather than in its myelin sheath, the site of
the problem in the type 1 forms.
The new gene, located on chromosome 1, is for a protein called mitofusin
2 (MFN2), which plays a role in the behavior of mitochondria,
the energy-producing units of cells and crucial contributors to the
health of the nervous system.
Previous research identified the gene for the protein known as kinesin 1B (KIF1B) as a culprit gene for CMT2A in one Japanese
family, but so far the MFN2 gene appears to be the more common cause
of the disorder.
"We conclude that mutations in MFN2 are the primary cause underlying
CMT2A," the investigators say in their paper. "The present study demonstrates
a new mechanism for axonal [nerve fiber] neuropathies [nerve diseases]
and should provide insight into the pathophysiology of neuropathic
disease, both hereditary and acquired."
Biotech Firm to Develop
Gene Therapy for Duchenne
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Xiao
Xiao |
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Virus
carrying DNA |
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MDA has awarded $1.6 million to the North Carolina biotechnology
company Asklepios to develop gene therapy for Duchenne muscular
dystrophy (DMD). Researchers Richard Jude Samulski, director of
the Gene Therapy Center of the University of North Carolina at Chapel
Hill, and Xiao Xiao, an MDA grantee and biologist in the Department
of Molecular Genetics & Biochemistry at the University of Pittsburgh,
are on the Asklepios team.
The company plans to develop and test a virus-based system designed
to deliver a miniaturized dystrophin gene to the muscles of boys with
DMD. Dystrophin is the muscle protein that's needed but missing in
this disease.
After extensive toxicology testing required by the U.S. Food and
Drug Administration, the company plans to conduct a phase 1 clinical
trial to test the safety of the compound in a small number of DMD-affected
boys.
Naked DNA Strategies
Advance for DMD Treatment
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Naked DNA |
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MDA grantee Jon Wolff in the Department of Pediatrics at the University
of Wisconsin Madison was on a team that announced at a June 2-6 meeting
of the American Society of Gene Therapy that it had made significant
progress in its intravascular approach to muscle gene transfer.
Wolff is working closely with Mirus, a Madison-based biotechnology
company that he co-founded and of which he is chief scientific officer.
Instead of using viruses to transport the genes, Wolff and colleagues
injected full-length, human dystrophin genes without viruses —
"naked" DNA — into a leg vein in four dystrophin-deficient mice
(an animal model for Duchenne MD). They applied a tourniquet
around the upper leg of each animal to keep the injected genes concentrated
in one area and targeted to that region's muscles.
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Jon
Wolf
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The researchers found that 3 percent to 15 percent of the leg muscle
fibers in the mice showed dystrophin production, while the expected
percentage of dystrophin-producing fibers in these animals would be
below 0.5 percent. The muscle groups in the back of the upper leg
showed the highest average dystrophin presence.
The investigators say the delivery method appears safe and effective
and doesn't seem to provoke an unwanted immune response, as viral
delivery sometimes does.
They've also experimented with other genes and with a compound called siRNA that can block unwanted gene activity. These experiments,
including ones in larger mammals, such as dogs and monkeys, have also
shown positive results.
Last year, the French Association Against Muscle Diseases (AFM),
in conjunction with the biotechnology company Transgene, of Strasbourg,
France, announced that naked DNA showed promise when it was injected
into the muscles (not the blood vessels) of 15 boys with DMD or the
closely related Becker MD.
A small amount of dystrophin protein was apparently produced from
the naked DNA construct, resulting in dystrophin showing up in between
1 percent and 10 percent of injected muscle fibers in the boys who
received the highest dose of the construct. (See "Naked
DNA," July-August 2003.) The researchers said the experiment showed
the construct is safe.
The intravascular approach is designed to increase the number of
muscle fibers showing dystrophin per injection of DNA.
MDA, Others Explore
Value of Steroid Use in DMD
MDA is supporting a study of high-dose, weekly prednisone in Duchenne
muscular dystrophy, compared to moderate-dose, daily prednisone.
The study, being conducted at several sites across the country, still
needs participants.
For more information, contact study coordinator Erik Henricson in
Washington at (202) 884-3813 or ehenricson@cnmcresearch.org.
A national clinical trials network, established by MDA in June, will
likely further investigate the use of corticosteroids in DMD.
This spring, two groups published reports of their preliminary conclusions
on the use of corticosteroids in (DMD), with recommendations for further
action.
Corticosteroids such as prednisone, prednisolone and deflazacort
(outside the United States) are commonly prescribed to prolong walking
in youngsters with DMD. So far, though, there hasn't been a consensus
on the optimal usage of these medications.
ENMC Report
A group of 35 participants from several European countries, the United
States, Britain and Canada convened in Naarden, the Netherlands, April
2-4, to discuss new directions for corticosteroid use in DMD. Among
them was Sharon Hesterlee, MDA's director of research development.
In a report that can be read in its entirety on the ENMC Web site
at www.enmc.org/workshops/reports.aspx?p=157,
the group concluded that there can "no longer be any doubt that the
use of steroids in ambulant [walking] children with DMD alters the
natural history of the condition."
The report also said that:
- children treated with daily steroids are likely to walk for longer,
have improved respiratory function, may avoid the need for spinal
surgery and might have better heart function than untreated children;
- there are significant side effects associated with prednisone
and deflazacort;
- alternatives to daily steroid dosages might mitigate side effects
and still provide benefits;
- a large-scale clinical trial to test different approaches to
steroid use is urgently needed;
- and, pending new information, boys with DMD on steroids should
be as active as possible, maintain proper levels of vitamin D and
calcium to minimize bone loss, and avoid sweets and fast foods to
control their weight.
Cochrane Review
Also published this spring is the Cochrane Collaboration's review
of multiple studies of corticosteroids in DMD.
The Cochrane Collaboration is a not-for-profit organization that
publishes quarterly reports on health care interventions based primarily
on analyses of randomized clinical trials — those in which participants
with the same characteristics are randomly assigned to a treatment
or nontreatment group and then compared.
Summaries of these reviews are available at www.cochrane.org,
and complete reviews are available for purchase through the Web site.
In issue 2, 2004, of the Cochrane Library, the reviewers discuss
corticosteroids for DMD, basing their analysis on five randomized
trials.
They found that:
- corticosteroids improve or stabilize muscle strength and function
for six months to two years;
- the most effective dose of prednisone or prednisolone appears
to be 0.75 milligrams per kilogram per day;
- adverse effects, such as excessive weight gain, behavioral abnormalities,
redistribution of body fat to the face and abdomen, and excessive
hair growth, are significantly more common in those taking steroids
but are not severe;
- the long-term benefits and hazards of corticosteroids in DMD
can't be evaluated from published studies;
- nonrandomized studies support the conclusions of functional benefits
but also indicate significant adverse effects with long-term steroid
treatment;
- and more studies are needed.
CLINICAL TRIALS AND
STUDIES
Creatine Shows Modest
Benefit in Duchenne MD
MDA grantee Mark Tarnopolsky at McMaster University in Hamilton,
Ontario, Canada, has completed a study of the dietary supplement creatine
in 30 boys with Duchenne muscular dystrophy (DMD). His results
are in the May 25 issue of Neurology.
His original study included patients with other types of muscular
dystrophy as well. In January 2004, he published partial results,
showing no benefit of creatine in type 1 myotonic dystrophy. (See "Research
Updates," March-April.)
In the DMD study, the researchers found that grip strength in the
dominant hand increased significantly in the creatine-treated boys
compared with those who took a placebo (inactive substance). Fat-free
body mass (mostly muscle mass) also increased, and a marker of bone
breakdown decreased. The supplement was well tolerated, and there
were no kidney or liver problems.
Other measures, such as pulmonary function, activities of daily living,
and the ability to perform functional tasks such as climbing stairs
or cutting a piece of paper with scissors, didnt show improvement.
Researchers
Seek Creatine Trial Participants
Other studies of creatine have had mixed results, depending on how
the study was conducted and which diseases were examined.
Jonathan Strober, who directs the MDA clinic at the University of
California at San Francisco, reported at the annual meeting of the
American Academy of Neurology, held April 24-May 1 in San Francisco,
that creatine was safe but not effective in various neuromuscular
disorders.
Strober's study didn't compare creatine to a placebo and looked at
two boys with DMD, two girls with limb-girdle MD and one girl
with an inflammatory nerve disease.
Strober has now opened a new, larger trial to study the safety of
creatine and seeks 18 participants, ages 4 to 18, with any muscle
or nerve disease. Participants will all receive creatine and be admitted
to UCSF Children's Hospital for three overnight visits during a three-month
period. They'll undergo blood and urine tests, as well as strength
and functional testing.
For details, contact Strober at (415) 502-4943 or stroberj@peds.ucsf.edu.
Sleepiness to Be
Studied in Myotonic MD
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Emma
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Emma Ciafaloni of the Department of Neurology at the University of
Rochester (N.Y.) Medical Center is directing an MDA-funded study of
excessive sleepiness (hypersomnolence) in type 1 myotonic dystrophy
(MMD).
The researchers are seeking 15 people with or without excessive daytime
sleepiness (a common problem in MMD). Participants must be willing
to spend three days and two nights at the medical center, where their
sleep will be studied, and where they'll undergo a lumbar puncture
to look at a chemical in the fluid around the spinal cord.
For information, contact James Hilbert, research coordinator, at (585)
273-5590 or through
james_hilbert@urmc.rochester.edu.
Study of FSHD Gene Recruiting Participants
Rabi Tawil in the Department of Neurology of the University of Rochester
(N.Y.) Medical Center is looking for people with facioscapulohumeral
muscular dystrophy (FSHD) to participate in a study to evaluate
the gene that, when flawed, causes the disease.
The study involves a one-time visit to obtain a blood sample and
a muscle sample via needle biopsy.
For information, contact Colleen Donlin-Smith, health project coordinator,
at (585) 275-7680 or Colleen_DonlinSmith@urmc.rochester.edu.
California Team to
Probe Episodic Muscle Disorders
Periodic paralysis (PP) and paramyotonia congenita (PC) are
among the "episodic" disorders — characterized by periodic attacks
with normal functioning between attacks — under study at the
University of California at San Francisco, under the direction of
Ying-Hui Fu and Louis Ptacek of the Department of Neurology. Epilepsy
and migraine headaches are also targets of the study team.
The investigators are seeking at least 500 people who have one of
these disorders or have a family member with one of these disorders.
Participants will need to donate a blood sample for DNA testing and
fill out a questionnaire describing the familys medical history.
For information, contact Beatrice Sorenson, clinical research coordinator,
at (415) 502-3976 or bsoren@itsa.ucsf.edu.
ALS Study Needs People With
Other Disorders
Finding the unique biochemical "signature" of amyotrophic lateral
sclerosis (ALS) in blood and other body tissues would speed diagnosis
of this paralyzing disease and would allow researchers to monitor
the effectiveness of experimental treatments more easily.
A study directed by Merit Cudkowicz in the Department of Neurology
at Massachusetts General Hospital in Boston, in concert with Metabolon,
a Durham, N.C., biotechnology company, will compare blood samples
from 100 people with ALS to healthy "control" samples and
samples from people with other disorders.
The investigators need samples from 50 people with inflammatory
muscle diseases, 50 with a disease of the peripheral nerves, 100 from people with Alzheimer's disease, and 100 from people without
a specific disease.
All participants must be older than 20, and all blood samples must
be drawn at Mass General.
For more information, contact study coordinator Kristyn Newhall at (617)
726-0653 or
knewhall@partners.org.
