Two Lines of Myotonic Dystrophy
Research Bear Fruit
This summer, two MDA-supported research groups published
findings that suggest possible approaches for treatment of type 1 myotonic dystrophy (MMD1),
a disease in which extra DNA on chromosome 19, when converted by
a normal process into RNA, leads to a cellular traffic jam with
wide-ranging effects on muscles and other organs. (A similar process
happens in type 2 myotonic
dystrophy, except that the problem is on chromosome
3 and the gene is called ZNF9.)
Weakness and myotonia (inability to relax muscles),
gastrointestinal distress, cardiac problems, cataracts, sleepiness
and sometimes cognitive difficulties all appear to stem from the
extra RNA in MMD-affected cells.
First, on July 24, a group that included
MDA grantee Maurice Swanson at the University of Florida-Gainesville
announced online in the Proceedings of the National Academy of Sciences
that it had overcome at least some of the effects of MMD1 in mice
by injecting genes into a leg muscle.
The genes carry instructions for the protein MBNL1, which is apparently
trapped in the nucleus of MMD-affected cells by extra-long strands
of RNA and prevented from carrying out its normal functions.
The treated leg muscles recovered from their myotonia, and, at
the same time, the processing of genetic information for four muscle
proteins, all of which are known to be abnormal in MMD1, was restored
to normal.
Some structural abnormalities in the muscle fibers persisted, a
problem Swanson speculates might be overcome by boosting MBNL1 levels
even higher.
In the next phase of the research, he says, the scientists plan
to inject MBNL1 genes into the bloodstreams of mice. “Myotonic
dystrophy patients want all their muscles corrected, not just one,”
Swanson says. “One way to get around this problem is to try
systemic injections.”
Then, on July 30, a group including MDA
grantee Mani Mahadevan at the University of Virginia in Charlottesville
announced its findings online in Nature Genetics.
Mahadevan and colleagues developed a new mouse model of type 1
MMD, one with many extra copies of the part of the DNA that’s
abnormally expanded in this disease. Instead of one long piece of
DNA, though, they bred the mice to carry several shorter pieces.
They also integrated a “switch” into the DNA, which
they could activate by giving the mice doxycycline, an antibiotic,
in their drinking water. When the activation switch was turned on,
cells in the mice began the normal process of transcribing the DNA
into RNA, but, because of the extra copies, they made about 10 to
15 times the normal amount of RNA.
Within a few weeks, the mice developed all the hallmarks of MMD1:
myotonia; a heart rhythm abnormality known as a conduction block;
and fetal, rather than adult, forms of several proteins.
When the doxycycline was stopped, the DNA was inactivated, and
the mice stopped transcribing it into RNA. The mice, surprising
the investigators, returned to normal in all respects, except in
cases in which the heart was very severely affected.
Mahadevan says the extra RNA pieces in these mice were both necessary
and sufficient to produce MMD symptoms, even though they didn’t
form the clumps of RNA and protein seen in the human form of the
disease and considered by many to be a major cause of these symptoms.
Getting rid of the extra RNA was enough to virtually cure the disease.
“If you take away the poisonous RNA the way we do it, by shutting
off the gene, no RNA gets made anymore, the muscles get better,
and the heart gets better,” Mahadevan says. Shutting off the
gene may not be possible in people, he notes, but the group has
other strategies in mind for targeting the toxic RNA.
New SMA Gene Mapped
Researchers in France have identified a new genetic
form of spinal muscular
atrophy (SMA), a disease in which motor neurons (nerve
cells) in the spinal cord and sometimes the brainstem degenerate.
Most cases of SMA are due to the inheritance of mutations
in each of a child’s two (one from each parent) chromosome
5 genes that instruct for the SMN protein. Another recessive (requiring
genetic flaws from both parents) form of SMA, with respiratory failure
occurring in the first weeks of life, results from mutations in
a gene on chromosome 11. But some people with SMA remain without
a genetic diagnosis.
Now, Isabelle Maystadt at Hopital Necker Enfants Malades
in Paris, and colleagues, have localized a region on chromosome
1 as containing the gene that, when mutated, can cause another recessive
form of SMA. Discovered by studying a large family originating from
Mali (near Algeria), this form looks similar to the familiar SMA
type 3, but it’s more severe and involves the breathing muscles
and muscles of the hands and feet.
The investigators, who published their findings in
the July 11 issue of Neurology, are trying to identify the specific
gene involved, which should allow more patients to obtain a specific
diagnosis. In addition, they say, “Identification of a new
gene will, it is hoped, contribute to a better understanding of
the molecular mechanisms involved in motor neuron degeneration.”
Compound Reverses Gene
Flaw in Cells With Friedreich's Ataxia
Investigators at the Scripps Research Institute in
La Jolla, Calif., and the University of California-Los Angeles have
identified a compound that can reverse the effects of the most common
genetic defect underlying Friedreich’s
ataxia (FA).
David Herman and colleagues, whose results were published
online Aug. 20 in Nature Chemical Biology, used an HDAC (histone
deacetylase) inhibitor molecule to reverse the “silencing”
of the gene for frataxin that occurs in FA-affected cells.
The silencing is thought to occur because of GAA repeat
DNA present on chromosome 9, which underlies this recessively inherited
disease in most people who have it. The GAA repeats cause a structural
change in the chromosome and alter the way the DNA is packaged in
the region of the frataxin gene, keeping it from being recognized
by the cell and used to make frataxin protein.
An HDAC inhibitor dubbed 4b blocked this disease-causing
effect, apparently exposing the frataxin gene to the cell’s
gene-reading mechanisms and allowing it to make frataxin RNA and
protein.
The researchers conducted a series of experiments
on white blood cells taken from FA patients and carriers, which
they grew in laboratory dishes and directly exposed to HDAC inhibitors.
When the cells from FA patients were exposed to HDAC
inhibitor 4b, their frataxin RNA levels increased to at least the
levels seen in FA carriers (who generally don’t have disease
symptoms). Frataxin RNA levels in 4b-treated carriers nearly doubled.
The investigators also determined that the cells could produce frataxin
protein from the new frataxin RNA.
“The next steps are to see whether the molecules
act as histone deacetylase inhibitors in animals, whether the molecules
increase frataxin messenger RNA and protein in a mouse model for
the disease, and whether the molecules are nontoxic to animals,”
said study team member Joel Gottesfeld, a professor of molecular
biology at Scripps. “Each of these steps must yield positive
results for these molecules to be considered true clinical candidates
for FA. Although our results are very encouraging, it will be many
months before we know the answers to these important questions.”
Scientists Determine Effects
of Nemaline Myopathy Mutation
MDA research grantee Alan Beggs, at Children’s
Hospital in Boston, was among scientists who recently uncovered
some of the consequences of a genetic mutation that causes nemaline
myopathy.
Despina Sanoudou and colleagues, who published their
findings in the Sept. 1 issue of Human Molecular Genetics, bred
mice with a mutation in the alphatropomyosin gene, which is one
of the causes of human nemaline myopathy. They found the downstream
consequences of this mutation are a pattern of muscle fiber degeneration
and regeneration, and a failure of the diaphragm muscle fibers to
mature properly.
Finding May Add New Cause
of Centronuclear Myopathy
Mice bred without genes for the protein gamma-actin
develop a muscle disease that in some respects resembles human centronuclear
myopathy (CNM), a disorder characterized by weakness and
misplacement of cell nuclei toward the center of the fiber, say
researchers at the University of Wisconsin and the University of
Maryland.
Researchers coordinated by MDA grantee James Ervasti,
now at the University of Minnesota-Twin Cities (although he performed
this work while at the University of Wisconsin-Madison), published
their results in the September issue of Developmental Cell.
The findings may add to the diversity of genetic mutations
and protein abnormalities that underlie CNM, which, until recently,
was considered synonymous with myotubular
myopathy (MTM). It was so named in the 1960s because
the muscle fibers’ appearance superficially resembles that
of immature fibers called myotubes.
In 1997, mutations in the gene for myotubularin, on
the X chromosome, were identified as the underlying problem in MTM,
now generally thought of as a severe form of CNM.
Last year, a team that included Alan Beggs, an MDA research grantee
at Children’s Hospital in Boston, identified mutations in
the gene for dynamin 2, on chromosome 19, as a cause of dominantly
inherited CNM. This form of the disease is generally milder than
the X-linked, myotubularin-related form.
In humans, the gamma-actin gene is located on chromosome
17. So far, no patients with gamma-actin-related CNM have been identified.
But Ervasti and colleagues write that their findings “support
the screening of genetically undiagnosed patients for [gamma-actin]
mutations.”
CLINICAL
TRIALS AND STUDIES
Moving Ahead in Myasthenias
In myasthenias, disorders in which the
transmission or reception of signals from nerve fibers to muscles is
disrupted, treatment has long centered around improving the strength
of the signal by prolonging the action of the chemical acetylcholine.
In cases where the underlying problem involves a renegade immune system,
treatment is also aimed at suppressing immune responses that interfere
with neurotransmission. Investigators are refining these strategies
to achieve more benefit with fewer side effects.
Value of Thymectomy in MG Being Tested
A multinational trial to determine the value of removing the thymus
as a treatment for myasthenia
gravis (MG) has opened at some 70 centers in the United
States, Europe and Asia.
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At the junction of nerve
and muscle cells, acetylcholine flows across a gap and lands on
receptors, which transmit muscle contraction signals. Any part
of the process can be disrupted, resulting in myasthenia. |
Removing the thymus, an organ of the immune system located in the
chest, involves surgery (thymectomy). It has long been used as a treatment
for MG, a disorder in which the immune system mistakenly attacks the
parts of muscle fibers that receive signals from the nervous system.
But until now, no systematic study has been conducted that measures
what, if any, benefit there is for patients in adding thymectomy to
standard MG medications, such as prednisone. This study is designed
to determine whether thymectomy provides additional control of MG
symptoms or reduces the amount of prednisone patients need.
The trial is seeking adults with MG who are between 18 and 60, are
willing to be randomly assigned to receive prednisone and a thymectomy
or prednisone alone, are willing to be studied for at least three
years, and meet other criteria.
For details, see www.soph.uab.edu/mgtx,
or call Greg Minisman at the University of Alabama-Birmingham at (205)
934-4905.
New Myasthenia Drug Under Study
The drug Monarsen (formerly EN101), developed by Ester Neurosciences
(www.esterneuro.com) in Herzelia,
Israel, is being studied in the United Kingdom under the direction
of Jon Sussman at Hope Hospital in Greater Manchester. If all goes
well, testing of the drug in people with myasthenias may be expanded
to the United States and Europe.
People with myasthenia gravis
(MG), Lambert-Eaton
myasthenic syndrome (LES) and some congenital
myasthenic syndromes (CMS) benefit from drugs that prolong
the action of acetylcholine at the junction of nerve and muscle fibers.
In MG, the immune system mistakenly attacks receptors for acetylcholine
on muscle cells. In LES, the immune system inhibits the chemical’s
release from nerve fibers. And in some CMS cases, the action of acetylcholine
is insufficient because of a genetic mutation that affects the neuromuscular
junction.
A common treatment for these diseases is pyridostigmine (Mestinon),
which interferes with the breakdown of acetylcholine by the enzyme
AchE. But pyridostigmine’s actions are limited, and, at high
doses, it can have unwanted side effects.
Monarsen targets AchE before it’s synthesized, while pyridostigmine
targets the finished protein. According to Ester Neurosciences, attacking
the finished protein stimulates the body to produce more AchE, triggering
a battle between the drug and the nervous system. In contrast, the
company says, Monarsen, which inhibits AchE synthesis, doesn’t
cause this vicious cycle.
The company says Monarsen also could have applications for amyotrophic
lateral sclerosis (ALS), a disease in which muscle-controlling
nerve cells die.
Sleep Apnea in MG Can Lead to Overmedication
A Canadian research group has found that a type of disturbed breathing
during sleep resulting from obstruction of the airway is probably
much more common in people with myasthenia
gravis (MG) than in the general population. They say
the problem, known as obstructive sleep apnea (OSA), may not always
be correctly identified.
Michael Nicolle of the London Health Sciences Centre in Ontario,
and colleagues, who published their findings in the July 11 issue
of Neurology, randomly selected 100 people with MG from 400 clinic
patients and assessed their risk of obstructive sleep apnea.
Fifty were identified as high-risk, and 37 agreed to undergo sleep
studies. Of those, 34 were found to have OSA, mostly due to weakness
of the mouth and throat muscles and mostly leading to episodes of
abnormally slow, shallow breathing. Two people in the low-risk group
were also found to have sleep apnea, yielding a total of 36 percent
of MG patients in this study with this condition.
The prevalence of OSA in the general population is estimated at 15
percent to 20 percent. The researchers say 36 percent is an underestimate
in MG, since 13 of the high-risk patients didn’t have sleep
studies.
Sleep apnea can lead to sleep deprivation and significant daytime
fatigue, which could be misinterpreted as resulting from overall worsening
of the person’s MG, the authors say. They caution, “Without
considering a role for OSA, a history of fatigue could lead to deleterious
increases in corticosteroids.”
The correct treatment for obstructive sleep apnea is usually delivery
of pressurized air by mask.
LGMD Gene Transfer Trial Slated for
Next Year
Neurologist Jerry Mendell, an MDA grantee at Columbus (Ohio) Children’s
Research Institute (CCRI), says he hopes to start a clinical trial by
mid-2007 that will test the safety of transferring the gene for alpha-sarcoglycan
into leg muscles of people with type 2D
limb-girdle muscular dystrophy (LGMD2D).
The trial, which is open to LGMD2D patients ages 5 and older, is under
the auspices of the National Institutes of Health, MDA and CCRI. Those
who think they may have LGMD2D can apply for the trial and undergo DNA
testing of their blood cells in Columbus. If they meet study criteria,
they may be asked to undergo a muscle biopsy as well.
The trial will last three months, and some help with travel expenses
may be available. For information, contact Xiomara Rosales at CCRI at
(614) 722-6961 or rosalesx@ccri.net;
or Jerry Mendell at (614) 722-5615 or mendellj@ccri.net.
Studies and Trials Target Myositis
Several studies for those with polymyositis, dermatomyositis or inclusion-body myositis are being sponsored by the National Institutes of Health (NIH) in Bethesda,
Md., as well as medical centers and pharmaceutical companies.
Drugs based on antibodies (immune system proteins) that block inflammation-causing
substances are under study in all three types of myositis. In addition,
a study of twins or sibling pairs in which only one has myositis, and
a comparison of blood components seek to improve understanding of these
disorders.
See www.clinicaltrials.gov and enter “myositis” in the search box; or contact the NIH
Patient Recruitment and Public Liaison Office at (800) 411-1222 or prpl@mail.cc.nih.gov.
Some trials are also posted on the MDA site at www.mda.org/research/ctrials.aspx
Unapparent Conditions Are Subject of Study
Arizona State University graduate student Aimee Burke, who has a form
of muscular dystrophy that’s “unapparent”
to most observers, is conducting a study of people who have a medical
condition that isn’t obvious to the unknowing observer.
The study will consist of two interviews, subjects will be paid $25
for each. Participants must be at least 20 and have had a diagnosis
or symptoms of an unapparent medical condition since age 13 or earlier.
Contact Burke at (623) 780-0049 or aimee.burke@asu.edu. |
