Research Updates
Protein Turns Average Mouse into Mighty Mouse
Nadia Rosenthal |
A new MDA-funded study shows that mice genetically engineered to overproduce a
muscle-building protein called muscle insulin-like growth factor 1 (mIgf1)
develop large, powerful skeletal muscles, and resist the muscle decay that
occurs during old age.
In old age, muscles waste away partly because "their capacity for regeneration
drops off. In some ways, that may mimic what happens in the later stages of
muscular dystrophy," says the study's lead researcher Nadia Rosenthal of
Harvard-affiliated Massachusetts General Hospital-East in Charlestown.
The effects of mIgf1 in mice suggest that supplying extra mIgf1 — perhaps via
gene therapy — might promote muscle regeneration in people affected by
age-related muscle frailty or by muscular dystrophy, Rosenthal says. Unlike
related Igf1 proteins, mIgf1 is made specifically by voluntary (or skeletal)
muscle and is normally stuck there, Rosenthal says. This focused action of
mIgf1 could make it a safe and effective treatment against muscle wasting,
Rosenthal suggested.
Genetically engineered mice that overproduce a different type of Igf1, she
pointed out, develop a general increase in muscle mass, and die from abnormal
enlargement of the heart. In contrast, Rosenthal's study, which appeared in the
February issue of Nature Genetics, shows that mice overproducing mIgf1 develop
normal cardiac muscle.
Rosenthal co-led the study with MDA grantee H. Lee Sweeney from the University
of Pennsylvania in Philadelphia. Other key contributors included Elisabeth
Barton, a member of Sweeney's lab, and Antonio Musaro, formerly in Rosenthal's
lab, but now a professor at the University of Rome "La Sapienza" in Italy.
The same team previously used a gene therapy technique to administer mIgf1 to
single muscles in aged mice, and found that the mIgf1 prevented wasting of the
treated muscles. They conducted the new study to determine whether large-scale
treatment with mIgf1 would be similarly beneficial.
They found that boosting mIgf1 promotes skeletal muscle regeneration in mice by
stimulating satellite cells, which can repair damaged muscle by replacing lost
muscle cells.
Some researchers have suggested that stimulating satellite cells as a way of
treating muscular dystrophy might quickly exhaust a person's supply of
satellite cells.
"Our data suggest that this is not the case in older muscle," Rosenthal says.
"Since our animals continue to regenerate [muscle] in later stages of life, it
appears that [satellite cells] can maintain the muscle in a healthy state.
"It remains to be seen if this will hold true in a disease state, but using
these animals we can begin to test that hypothesis vigorously," she added.
Toward that goal, Rosenthal and her team plan to crossbreed the mIgf1-producing
mice with mice that have muscular dystrophy.
If mIgf1 proves beneficial to those offspring the researchers estimate that
clinical trials of mIgf1 for muscular dystrophy could begin in as little as two
years.
Boosting Integrin Could Be Treatment for Dystrophies
Stephen Kaufman |
New experiments show that when mice genetically engineered to lack the muscle
proteins utrophin and dystrophin were bred to produce more than the usual
amount of a protein known as alpha-7-beta-1 integrin, they didn't develop the
type of severe muscular dystrophy seen in utrophin- and dystrophin-deficient
mice.
MDA grantees Stephen Kaufman and Dean Burkin in the Department of Cell and
Structural Biology at the University of Illinois at Champaign-Urbana were on a
team that published results in the March 19 issue of the Journal of Cell
Biology. They suggest that boosting integrin levels would be a good strategy to
pursue for the treatment of several types of muscular dystrophy involving
muscle membrane proteins, including Duchenne and Becker dystrophies, the
sarcoglycan-deficient forms of limb-girdle dystrophy, and the laminin- and
integrin-deficient forms of congenital muscular dystrophy.
In general, integrins form an anchoring bridge between the cytoskeleton
(scaffolding) of cells and proteins outside the cells. The form of integrin the
research team used may help the muscle membrane remain intact by compensating
for defects elsewhere in the membrane.
Strategies to boost integrin could involve either gene therapy — inserting extra
genes for integrin — or a drug treatment to increase production of integrin
from a person's existing integrin genes.
New Drugs May Help in Autoimmune Diseases
Two new drugs, one already on the market, show promise in treating two
autoimmune diseases affecting muscles. Autoimmune diseases are disorders in
which the body's immune system attacks its own tissues.
Two studies conducted at MDA clinics at Duke University in Durham, N.C., and
Johns Hopkins University in Baltimore show that mycophenolate mofetil is
effective and apparently safe in myasthenia gravis (MG). Mycophenolate mofetil,
marketed as CellCept by Roche Pharmaceuticals, was developed to prevent immune
system rejection of transplanted organs and has recently been studied in
various autoimmune disorders.
Daniel B. Drachman |
Daniel B. Drachman, director of MDA's clinic at Johns Hopkins who was part of
one MG study, says, "Our experience is that, for most people, it works, and it
allows you to diminish the corticosteroid dose used. In some people, it does
the whole job. The beauty of it is that, for most people, it has virtually no
adverse side effects."
Corticosteroids such as prednisone, a mainstay of treatment for MG, can cause
weight gain, fluid retention, bone loss, psychological disturbances and many
other problems. Other drugs that suppress the immune system, such as
azathioprine (Imuran), cyclosporine (Sandimmune, Neoral), and cyclophosphamide
(Cytoxan), also can have serious side effects, such as kidney damage or
increased cancer risk.
In an immune response, helper T cells divide and multiply,
and they signal cytotoxic T cells and B cells to do the same. Cytotoxic T cells
can kill other cells directly, while B cells make proteins called antibodies,
molecular "bullets" that attack cells. When antibodies stick to a targeted
tissue, they can activate complement proteins, another weapon in the immune
system's arsenal. Mycophenolate mofetil (CellCept) blocks the replication of T
and B cells, while complement inhibitor blocks the activation of complement
proteins. Both drugs fight the immune response, the mistaken action that leads
to autoimmune diseases. |
|
The Johns Hopkins study included 32 people with MG, of whom 22 improved on
mycophenolate mofetil; the Duke study included 12 people with MG, of whom eight
improved on the drug. Many people were able to reduce prednisone dosages.
Emma Ciafaloni, MDA clinic co-director at Duke University,
was part of the mycophenolate mofetil study. |
The results of both studies are in the Jan. 9 issue of the journal Neurology.
Because the drug is expensive and isn't always covered by insurance, Roche has a
program to assist with costs. The prescribing physician can call (800) 772-5790
for more information.
In another study, Alexion Pharmaceuticals of Cheshire, Conn., is investigating a
new type of drug for autoimmune disease and has made dermatomyositis (DM) one
of its treatment targets.
The company has developed a protein that blocks the full activation of
complement, which is the end result of a chain reaction involving some 30
proteins. These proteins participate in some immune responses, including the
response thought to underlie DM.
The Alexion drug, which goes by the designation h5G1.1-mAb, or complement
inhibitor, blocks a key step in the process that would otherwise result in
cellular destruction in the targeted tissue.
Alexion is looking for more people to complete its 15-person study of adults who
have had DM for at least six months. For more information, have your physician
call Alexion at (203) 272-2596. Alexion's Web site is www.alexionpharm.com.
New Membrane Stabilizer Might Treat DMD/BMD
Duchenne and Becker muscular dystrophies (DMD/BMD) might one day be treated with
a versatile drug that can seal tears in the membranes (coatings) that surround
cells.
P188 might help prevent muscle degeneration
in DMD/BMD by plugging holes in the muscle cell membrane. |
In DMD and BMD, muscle cells break down because of a genetic deficiency in
dystrophin, a protein that's normally attached to the internal side of muscle
cell membranes. It's not clear why loss of dystrophin is so detrimental, but
many researchers believe the protein helps protect muscle cell membranes from
the physical stress of contraction. Indeed, holes in the membrane are sometimes
the only obvious sign of muscle damage early in the disease course.
MDA-funded researcher John Quinlan believes that Polaxymer 188 (P188) — a
synthetic substance that shares many of the chemical properties of cell
membranes — might be used to patch those holes and prevent further muscle
damage.
P188 was originally intended for use in the food industry, but scientists think
it might be used as a "membrane stabilizer" for treating several medical
conditions.
Cytrx, a biotech company in Norcross, Ga., that manufactures clinical grade
P188, has used it to treat critical episodes of sickle cell anemia, during
which red blood cells become so fragile that they actually burst open. The drug
has also been used to prevent damage to heart muscle cells during cardiac
arrest.
In collaboration with Cytrx, Quinlan, who's at the University of Cincinnati in
Ohio, plans to determine whether P188 can alleviate muscular dystrophy in mice
that don't have enough dystrophin.
If it works, P188 would have some advantages over other DMD/BMD treatments on
the horizon, Quinlan says. "One of the major problems with gene therapy and
stem cells is how to deliver them everywhere. P188 can be given systemically
[by IV injection] to all skeletal and cardiac muscle," he says.
If P188 shows promising results in the mice, Quinlan says, it could move to
clinical trials for DMD or BMD in a year and a half.
High-Dose Weekly Prednisone May Work in Duchenne Dystrophy
Giving the corticosteroid prednisone just two consecutive days a week at a very
high dose instead of every day at a lower dose may offer boys with Duchenne
muscular dystrophy (DMD) the benefits of the drug with fewer side effects, say
researchers at Washington University in St. Louis. Improvement in strength was
similar to that seen with the daily regimen.
Anne Connolly, an MDA grantee in the university's Departments of Neurology and
Pediatrics, cautions that these results are preliminary and that some patients
experienced irritability and stomach problems. The findings were announced at a
recent meeting of the Child Neurology Society.
New Genes Discovered for Myasthenic Syndrome and Periodic
Paralysis
Two recent discoveries might lead to better diagnosis and treatment for rare
forms of congenital myasthenic syndrome (CMS) and periodic paralysis (PP). Both
are genetic diseases that cause fluctuating muscle weakness by interfering with
muscle contraction.
Muscle contraction occurs when ACh released
from the nerve cell stimulates opening of ion channels in the muscle cell. In
CMS-EA, deficiencies in the CHAT enzyme result in insufficient ACh, and in rare
types of PP, potassium ion channels are defective. |
Normally, muscle contraction occurs when nerve cells send muscle cells a
chemical signal called acetylcholine or ACh. In most cases, CMS is caused by
genetic defects that alter the muscle cells' response to ACh.
Now, MDA grantee Andrew Engel has found that CMS with episodic apnea (CMS-EA) is
caused by defects in choline acetyltransferase (CHAT), the enzyme responsible
for manufacturing ACh within nerve cells. Engel, who's at the Mayo Clinic in
Rochester, Minn., reported that finding in the Feb. 13 issue of Proceedings of
the National Academy of Sciences.
In another MDA-funded study, Louis Ptacek at the University of Utah in Salt Lake
City identified a new genetic defect that causes PP.
Previously, Ptacek and other MDA-funded researchers helped establish that PP
usually results from genetic defects in ion channels that control the flow of
sodium and calcium in muscle cells. Now, Ptacek has found that unusual types of
PP are caused by defects in MiRP2, a component of ion channels that control the
flow of potassium. That finding was reported in the Jan. 26 issue of Cell.
Engel and Ptacek suggest that people who have symptoms of CMS or PP, but have
tested negative for the most common genetic defects, might have one of these
rare disease forms. Not only that, better treatments for these rare forms may
be around the corner, since effective drug therapies for common forms of CMS
and PP quickly followed identification of their underlying defects.
Cells Coaxed to Skip Over Genetic Error in DMD Mice
MDA grantee Stephen Wilton at the Australian Neuromuscular Research Institute at
the University of Western Australia in Perth was part of a research team that
developed a new type of gene therapy strategy in mice. The results are
published in the Jan. 2 issue of Proceedings of the National Academy of
Sciences.
Using chemicals known as antisense oligoribonucleotides (AOs), the re-searchers
changed the way muscle cells in mice with Duchenne muscular dystrophy (DMD)
processed their dystrophin genes. DMD in humans is caused by any of a number of
mutations (changes) in the gene for the muscle protein dystrophin, including
mutations of the type affecting these mice.
When the AOs, linked to a fatlike substance, were injected into the leg muscles
of the animals, mice that usually produce no dystrophin produced a modified
form of dystrophin that the researchers say would probably be at least
partially functional.
The AOs apparently blocked the cells' usual "reading" of the part of the
dystrophin gene containing the mutation, and allowed the cells to read most of
the remaining genetic instructions for the dystrophin protein.
The effects of the AOs are similar to those of the drug gentamicin, which also
changes the way cells read genes. Gentamicin is being tested in clinical trials
in people with DMD and in people with limb-girdle MD who have a specific type
of genetic mutation. (For information on the gentamicin trial, go to "Research, Active Clinical Trials.")
Prednisone With IVIG Doesn't Help in IBM
A three-month study conducted by Marinos Dalakas at the National Institutes of
Health in Bethesda, Md., and others, found that combining the corticosteroid
prednisone with intravenous immunoglobulins (IVIG) didn't benefit people with
inclusion-body myositis (IBM). The results are published in the Feb. 13 issue
of the journal Neurology.
Prednisone alone and immunoglobulins alone have likewise failed to allow
sustained improvement in IBM.
Both treatments are frequently used to treat autoimmune and inflammatory
disorders, and there has been speculation that the muscle loss and weakness in
IBM may result, at least in part, from inflammation. Other treatment avenues
are now being explored (see "Advances in
Inclusion-Body Myositis").
CMT Update: New Genetic Clues Found
At last count, researchers had identified seven genes linked to
Charcot-Marie-Tooth disease (CMT) (see "From
Clear-Cut Endings to Complex Beginnings," Quest, vol. 8, no. 1). But in
the past few months, they've found two new genes involved in CMT and the
related Dejerine-Sottas disease (DS) and hereditary sensory neuropathy type 1
(HSN1).
All three diseases cause some level of muscle weakness and sensory impairment
because of a breakdown of the peripheral nerves.
The seven previously identified CMT genes — some of which have also been linked
to DS — make proteins needed in one of two parts of the nerves: either the
axons (the "wires" inside the nerves), or the myelin (the insulation around the
wires).
Now, genetic defects in a myelin protein called periaxin have been linked to
certain types of CMT and DS. MDA grantee James Lupski at Baylor College of
Medicine in Houston reported the DS link in the February issue of the American
Journal of Human Genetics, and a European group reported the CMT link in the
Feb. 15 issue of Human Molecular Genetics.
In another MDA-funded study, Garth Nicholson at the University of Sydney in New
South Wales, Australia, identified the first known genetic defects for HSN1.
Those defects boost the action of the serine palmityl transferase protein
(SPT), which normally helps to make cell membranes, but becomes toxic when it's
overactive. That study was published in the March issue of Nature Genetics.
Rochester Group to Study Effects of Mexiletine in Myotonic
Dystrophy
Researchers at the University of Rochester (N.Y.) will study the effects of
mexiletine (Mexitil) on myotonia, the inability to relax muscles at will, in
myotonic muscular dystrophy (MMD). The drug, which affects how sodium enters
cells, is usually used to treat heartbeat abnormalities.
In addition to having MMD and experiencing grip myotonia, participants must be
between 18 and 80, be free of certain heart problems and meet other study
criteria. The study requires six to seven visits of two to four days each to
the University of Rochester Medical Center.
For more information, contact Cheryl Barbieri, research nurse, at (716) 275-5409
or send e-mail to neuro_research@urmc.rochester.edu.
New Mouse Models Created for FA, SBMA and LGMD1C
A trusted research strategy for understanding a genetic disease and testing
possible treatments is to create a mouse model — a mutant mouse with the
disease.
But for some diseases — including Friedreich's ataxia (FA), spinal bulbar
muscular atrophy (SBMA) and limb-girdle muscular dystrophy type 1C (LGMD1C) —
reproducing a human disease in a mouse has proved especially challenging.
Recently, researchers succeeded in creating mouse models for all three
diseases.
The FA mouse was created by MDA grantee Michel Koenig at the Institute of
Genetics and Molecular and Cellular Biology in Strasbourg, France. It's
described in the February issue of Nature Genetics.
The SBMA mouse was created by MDA grantee Diane Merry at Thomas Jefferson
University in Philadelphia, and is reported in the Jan. 15 issue of Human
Molecular Genetics.
The LGMD1C mouse was created by researchers in Japan, who published their study
in the Feb. 1 issue of Human Molecular Genetics.
Hibernating Bears May Hold Muscle Preservation Clues
Humans who are immobilized for months at a time lose a great deal of strength,
but hibernating bears, which don't move for five to seven months, remain fairly
strong. An immobile bear loses about 23 percent of its strength over 130 days,
while a human, it's estimated, would lose about 90 percent.
In a paper published in the Feb. 22 issue of Nature, Henry Harlow of the
Department of Zoology and Physiology at the University of Wyoming in Laramie
speculates that the bears may have biochemical methods, such as ways of
recycling nitrogen, that prevent severe strength loss. Understanding these
methods could have implications for the treatment of muscle diseases.
New Registries Slated for Myotonic, FSH Dystrophies
To accelerate progress toward treatments for myotonic dystrophy (MMD) and
facioscapulohumeral muscular dystrophy (FSHD), scientists are developing a
national registry of people affected by the two diseases.
Scientists have struggled to develop treatments for these two dystrophies
because both involve complex genetic mutations and symptoms that vary from
person to person.
By collecting medical information from people affected by the two diseases
nationwide, the registries will enable scientists to match specific mutations
with specific symptoms, and to recruit patients for large studies and clinical
trials.
The registry is being orchestrated by Richard Moxley III, co-director of the MDA
clinic at the University of Rochester (N.Y.), and is expected to begin
enrolling patients in the fall. Participation is voluntary.
For more information about the MMD/FSHD registry, contact registry coordinator
Lynn Cos by e-mail at lynn_cos@urmc.rochester.edu or by phone at (716) 275-7680.
Creatine Requires Caution, But Cancer Not Likely
Earlier this year, a French drug regulatory agency (Agence Francaise de Securite
Sanitaire des Aliments, or AFSSA) issued an advisory about potential health
risks, including a possible cancer risk, in taking creatine, a dietary
supplement available over the counter in the United States and widely used as a
purported muscle-building agent.
MDA-supported neuromuscular disease experts say there's no evidence of health
risks with creatine for people taking it in clinical trials for neuromuscular
diseases or under the supervision of their physicians.
The statement released by the French doesn't address the use of creatine by
people with neuromuscular disorders who are under medical supervision. It's
aimed at healthy subjects attempting to increase their athletic
performance. 
More MDA Research News
For up-to-the-minute news on MDA research developments, visit
MDA's Web site at www.mdausa. org.
Click on "Research" for
information on recent research developments and active clinical trials, and links to major medical/ research sites.
Look at the Web site's "What's New"
section for news bulletins about breaking research announcements. |
