QUEST Volume 9, Number 5, October 2002
Restrained enthusiasm might best describe the reaction of investigators to
muscle biopsy analyses performed on a 15-year-old boy with Duchenne muscular
dystrophy (DMD) who underwent a bone marrow transplant procedure at the
age of 1 year for an unrelated condition. The course of the boy's DMD was less
severe than average, and researchers had speculated that the transplant procedure
might have inadvertently treated his muscle disease as well as his other disease
(an immune system problem).
Now the results are in, and they bring good and bad news. The good news is that some of the bone marrow cells apparently fused with the boy's muscle fibers and persisted when muscle samples were examined 13 years later.
The investigators, including MDA-supported Louis Kunkel and Emanuela Gussoni of the Division of Genetics at Children's Hospital in Boston, say this indicates there are probably cells present in adult bone marrow that can
The bad news is that very few of the teen-ager's muscle fibers less than 1 percent contained cells from the transplant.
The authors of the paper, published in the Sept. 15 issue of the Journal of
Clinical Investigation, also found that the boy in this study has a genetic
mutation in his dystrophin gene that sometimes allows for a very mild course of DMD. They
say the slow progression of his disease is more likely due to the presence of shortened
but partly functional dystrophin protein, rather than to the presence of full-length
dystrophin, which would have been made by the transplanted cells.
"There is recruitment of cells from the circulation into muscle,"
Kunkel commented. "The efficiency is low, but the fact remains that it
happens, and we need to make it work better. This demonstrates the plasticity
[flexibility] of bone marrow cells in humans."
He noted that "this is an important patient, because we document that bone-marrow-derived cells can target muscle. We just need to increase the uptake before this would be considered for human experiments."
An open-label trial (not placebo-controlled) of the oral form of the drug albuterol
in 13 children with spinal muscular atrophy (SMA) suggests that it may
increase muscle strength and mass in that disease.
The study, conducted at the Imperial College School of Medicine in London by
Francesco Muntoni and colleagues, and published in the Aug. 27 issue of Neurology,
involved five children with type 2 SMA and eight with type 3 SMA.
After six months on albuterol, the group improved in muscle contraction strength, forced vital capacity (a respiratory measurement) and lean body mass on average.
There were no significant adverse effects. However, nine participants showed decreased mobility in their joints after six months, which the researchers say may have been due to selective strengthening of some muscles over others.
Larger placebo-controlled trials are needed to confirm these observations,
the study authors say.
John Kissel, a neurologist who co-directs the MDA clinic at Ohio State University
in Columbus and has MDA support to study albuterol in facioscapulohumeral
muscular dystrophy, says he found the study "provocative."
Kissel noted that "albuterol might be acting at a nonmuscle level," citing research in animals that suggests it could affect nerves. He'll explore the possibility of testing albuterol in SMA, but he cautions that there have been serious obstacles to obtaining the oral form of the drug (necessary to treat neuromuscular disease) in the United States.
The potent immunosuppressant drug cyclophosphamide (brand names Cytoxan and
Neosar), intravenously given for short bursts (two hours at a time), may allow
people with severe myasthenia gravis (MG) to control their disease symptoms
without high doses of corticosteroids, such as prednisone. The findings are
from a study conducted at Hospital Maria Ferrer in Buenos Aires, Argentina,
and are published in the July issue of Muscle & Nerve.
Nestor Mofino and colleagues looked at 23 people with MG whose disease was
either poorly controlled or who had developed serious corticosteroid-related
side effects, and gave them intravenous cyclophosphamide or placebo (inert substance
with no expected effect).
After the year-long study period, five subjects on cyclophosphamide were off
corticosteroids, whereas no subject on placebo was. Four cyclophosphamide-treated
participants were off steroids three years after completing the trial.
In those on the study drug, strength improved and no significant increase in
drug-related side effects occurred. However, one person developed bladder cancer
two years after the study, which the investigators say may have been related
to the drug.
The authors say the results support the view that pulsed-dose cyclophosphamide can be considered an effective, relatively safe and inexpensive alternative in MG. They caution that long-term follow-up of patients is necessary to detect any possible late-developing problems, such as cancer.
Investigators at eight U.S. medical centers have begun recruiting 80 participants
for a study of the drug mycophenolate mofetil (MM, brand name CellCept) in combination
with low-dose prednisone in myasthenia gravis (MG).
Participants must be at least 18, must have never taken immunosuppressive medications
for MG and must not have had a thymectomy (removal of the thymus) within the
previous year. Certain diseases also disqualify participants.
The study is supported by the U.S. Food and Drug Administration and Roche Pharmaceuticals.
There will be no cost for medications, clinic visits or blood tests, but participants
will be responsible for transportation costs.
For more information, contact Bernadette Lipscomb at Duke University Medical Center in Durham, N.C., at (919) 681-5176 or e-mail: lipsc002@mc. duke.edu; or visit www.mdausa.org/research/ctrials.html.
Two recent studies help explain why getting gene therapy for the muscular dystrophies
from lab bench to bedside has turned out to be a slow process. One shows that
over the long term, the immune system could neutralize the introduced gene,
and the other shows that the gene itself could become toxic if it's delivered
In the first study, mice with Duchenne muscular dystrophy (DMD) were
given a single intramuscular injection of adenovirus carrying the mouse gene
for dystrophin (the protein missing in DMD) and then monitored for more than
a year after injection. Most previous studies of gene therapy for DMD have followed
mice with the disease for up to several months after treatment.
When given to newborn mice, the injection increased dystrophin levels and slowed
degeneration in the injected muscle for up to 53 weeks. But when mice received
the injection as adults, after signs of DMD had already appeared, dystrophin
levels declined after just eight weeks and the injected muscle continued to
degenerate as though it hadn't been treated.
In both newborn and adult mice, the immune system responded to dystrophin as
if it were a foreign protein. (Adult mice also had an immune response to the
adenovirus, which may have boosted the response to dystrophin.)
The study, published in the September issue of Molecular Therapy, isn't necessarily
bad news for DMD gene therapy. Instead, "it represents part of an important
process in understanding the complexities of bringing gene therapy for muscular
dystrophy to a clinical reality," said lead researcher Paula Clemens, an
MDA grantee at the University of Pittsburgh. Her lab is investigating whether
co-delivery of genes encoding immunosuppressant proteins can curb the immune
response against dystrophin.
The second study, led by Eric Hoffman at Children's National Medical Center
in Washington, tested gene therapy in mice lacking either alpha-sarcoglycan
or beta-sarcoglycan. In humans, deficiencies of these proteins cause two of
the most common types of limb-girdle muscular dystrophy: LGMD2D and LGMD2E.
Devin Dressman, a research associate in Hoffman's lab, gave mice lacking either
of the proteins a single intramuscular injection of adeno-associated virus (AAV)
carrying the appropriate sarcoglycan gene. The method was effective at preventing
muscle degeneration in young beta-sarcoglycan-deficient mice, even nearly two
years after injection the longest-lived gene rescue ever observed for
a muscle disease.
But to the investigators' surprise, the treatment was toxic to muscle in alpha-sarcoglycan-deficient
mice. Further experiments showed that the toxicity wasn't caused by an immune
reaction to alpha-sarcoglycan, but most likely by an excess of the protein within
"The good news is that if beta-sarcoglycan delivery is as efficient in
humans as it is in mice, then a single injection could be enough to last the
lifetime of a patient in the treated region of muscle," Dressman said of
the results, published in the September issue of Human Gene Therapy.
He's adjusting the delivery system to decrease the level at which the alpha-sarcoglycan gene is expressed ("turned on") in muscle. A previous study from Kevin Campbell's lab at the University of Iowa in Iowa City reported successful correction of alpha-sarcoglycan deficiency in mice for up to seven months, using adenovirus to deliver the gene.
Medications used to lower blood cholesterol levels are associated with a somewhat
increased risk of damage to nerves and muscles, studies say.
The so-called statin drugs, with names like atorvastatin (Lipitor), fluvastatin
(Lescol), lovastatin (Mevacor), pravastatin (Pravachol) and simvastatin (Zocor),
are taken by millions of middle-aged and elderly people and are considered highly
beneficial in protecting against cardiovascular disease when dietary and other
lifestyle measures fail.
However, several studies, including a large Danish study reported by David
Gaist and colleagues in the May 14 issue of Neurology, suggest a needed increase
in awareness of potential side effects of these popular drugs.
The Danish study found a slightly increased risk of nerve damage, while other studies (such as one in the September 2001 issues of Annals of Pharmacotherapy and the journal Epidemiology) have concentrated on muscle damage. All studies so far have been done in patients without any underlying neuromuscular disease.
It isn't clear that people with neuromuscular diseases are unusually susceptible to the nerve- or muscle-damaging effects of statins. However, a worsening neuromuscular disease in someone taking a statin medication could be a warning. Unusual muscle pain or cola-colored urine in someone on a statin may indicate acute muscle destruction and should prompt an immediate call to a physician.
"Statins need to be added to the list of potentially contraindicated medications
in patients with any type of neuropathy [nerve problem] or any type of muscle
disorder, but especially in patients with Charcot-Marie-Tooth disease,"
noted Carlos Garcia, a specialist in nerve and muscle diseases who heads the
MDA clinic at Our Lady of Lourdes Hospital in Lafayette, La.
In type 1 spinal muscular atrophy (SMA), a severe, infant-onset disease
of the muscle-controlling nerve cells, parents are usually told that their children's
life expectancy is only 2 years and that extraordinary measures, such as assisted
ventilation, probably shouldn't be undertaken.
Now, John Bach in the Department of Physical Medicine and Rehabilitation at
the University of Medicine & Dentistry of New Jersey in Newark, has published
a study of 56 children with type 1 SMA suggesting that ventilation can prolong
survival. Bach, who co-directs the MDA clinic at UMDNJ, published his paper
in the July issue of Pediatric Pulmonology.
Bach prefers to treat respiratory muscle weakness in SMA with a program of
noninvasive ventilation delivered by mask or other user interface that
doesn't require a surgical opening. He uses noninvasive ventilation for as many
hours around the clock as needed, with mechanically assisted coughing and careful
monitoring of blood oxygen levels without using supplemental oxygen. He prefers
to use a tracheostomy tube or insertion of a tube down the throat (intubation)
only in emergencies and, when possible, only temporarily.
In Bach's study, which took place between June 1996 and October 2001, 46 of
the original 56 patients survived at the end of the study period.
Ten participants died one who had undergone a tracheostomy, two on noninvasive
ventilation, and seven who were intubated and whose parents were advised to
discontinue respiratory treatment and allow death to occur. Bach describes this
group as "not treated."
As of August, the oldest of the 46 survivors, who had a tracheostomy,was still
alive at age 19; one child on noninvasive ventilation was 8.
In a separate study, published in the June issue of the American Journal of
Physical Medicine & Rehabilitation, Bach also got favorable results in a
noninvasive ventilation program for people with Duchenne muscular dystrophy
(DMD). Bach and a Spanish researcher found that full-time noninvasive ventilation,
combined with mechanically assisted coughing and oxygen level monitoring, compared
favorably with tracheostomy-delivered ventilation in boys with DMD on several
measures, including pulmonary complications, hospitalizations, safety, convenience,
speaking ability, sleep, swallowing, appearance, comfort and expense.
The authors say none of the 34 people using the program underwent tracheostomy
or died from respiratory complications during the study period (an average of
about five years), although three died from heart failure. When those 34 people
were compared to a group that hadn't had access to Bach's program, it was found
that 31 had died while using noninvasive ventilation, 20 from respiratory causes,
seven from cardiac causes and four from other causes.
Bach is on staff at the Center for Noninvasive Mechanical Ventilation Alternatives at UMDNJ. For more, visit www.theuniversityhospital.com/ventilation.
Preoperative testing for a serious adverse reaction to general anesthesia may improve if the results of a study by Martin Anetseder and colleagues at the University of
The reaction, knownas malignant hyperthermia (MH) because of its ability
to cause body temperature to rise dangerously, is somewhat more common in people
with neuromuscular diseases, particularly central core disease, than in
the general population.
At present, testing for MH susceptibility generally requires a muscle biopsy,
although in some families genetic testing using a blood sample can suffice.
The test now under investigation simplifies the procedure to an intramuscular
injection of caffeine and subsequent measurement of blood carbon dioxide levels.
The German team found a marked difference in the carbon dioxide levels between
those known to have MH susceptibility and those known not to, as well as between
those with MH susceptibility and a group of healthy people not tested for MH.
However, the study involved only 27 people, a relatively small number. The results
are published in the May 3 issue of The Lancet.
It's an accepted fact that mitochondrial DNA passes strictly from mother to
child or at least it used to be until a new study reported evidence for
paternal transmission of mtDNA.
The study, published in the Aug. 22 issue of the New England Journal of Medicine,
"is interesting and important in that it breaks a dogma," says Salvatore
DiMauro, an expert on mitochondrial genetics and a longtime MDA grantee at Columbia
University in New York. The study also has implications for mitochondrial
Mitochondrial DNA (mtDNA) is the genetic material used to make essential proteins
inside mitochondria, the tiny factories that provide our cells with energy.
Mutations in mtDNA can cause diseases that involve muscle weakness, exercise
intolerance and other symptoms.
Textbooks and scientific articles alike say that mt-DNA can pass only from
mother to child because during conception, the egg destroys much of the sperm,
including its mitochondria. But in the NEJM study, Marianne Schwartz and John
Vissing of the University Hospital Rigshospitalet in Copenhagen, Denmark, show
that paternal mtDNA can sometimes survive this process.
Schwartz and Vissing made their discovery during a diagnostic workup on a patient with mitochondrial myopathy. They found a small "point" mutation in mtDNA
Still, the authors suggest that in some cases of mtDNA disease, the mutations
themselves might be paternally derived.
It's an astonishing possibility, but one without much practical significance, DiMauro says. "For 14 years, the maternal inheritance of point mutations in mtDNA has been well documented," he points out. "So, maternal inheritance will remain the rule."
The U.S. Food and Drug Administration has created a new department within its
Center for Biologics Evaluation and Research (CBER) that will combine gene-,
cell- and tissue-based therapy regulation, an FDA spokeswoman says. The new
Office of Cellular, Tissue and Gene Therapies, which became official Oct. 1,
combines the work of different departments.
"It's an attempt to better group the products and deal with the emerging science in a more consolidated manner," CBER's deputy director for operations, Mark Elengold, said in the July issue of Nature Medicine. Phil Noguchi, now Division Director of Cell and Gene Therapy, is acting director of the new center.
Efforts to keep the heart muscle from thickening abnormally a condition
known as hypertrophic cardiomyopathy (see "The
Heart Is a Muscle, Too," Quest, 1999, no. 2) just took another
step forward, says a study in the Aug. 23 issue of Cell. Hypertrophic cardiomyopathy
can occur when the heart is under physiologic stress, as it is in many types
of muscular dystrophy, particularly Duchenne and Becker MDs. Friedreich's
ataxia also causes this kind of cardiomyopathy. The thickening keeps the
heart from relaxing and contracting normally and can lead to heart failure with
The investigators, who are in the Department of Molecular Biology at the University
of Texas Southwestern Medical Center in Dallas, the Cardiovascular Division
of the University of Iowa College of Medicine, and Iowa City Veterans Affairs
Medical Center, included Eric Olson at UT Southwestern, who has MDA support
to study muscle regeneration.
In experiments with mice, the research team found that a group of natural body chemicals known as class 2 HDACs can prevent the deadly cardiac enlargement process. But, the team also found, they can be restrained from doing so by a natural enzyme that swings into action under stress. The researchers say the enzyme could theoretically be blocked, which might prove to be a way to prevent cardiac enlargement.
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