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QUEST Volume 9, Number 5, October 2002

Research Updates


Good News, Bad News on Stem Cells for Duchenne MD

Some stem cells from the bone marrow can apparently migrate into skeletal muscle, but their numbers are small.

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
Louis Kunkel
become muscle cells.

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."

Albuterol May Increase Muscle Strength, Mass in Children With SMA

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.

John Kissel

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.

IV Immunosuppressant May Allow Reduced Steroids in Myasthenia Gravis

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.

New Drug Study in MG

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.

MD Gene Therapy Hurdles Not Insurmountable, MDA Researchers Say

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 excess.

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.)

Paula Clemens

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 muscle cells.

"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.

Statins Can Cause Nerve and Muscle Problems

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.

Carlos Garcia

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.


Noninvasive Ventilation Can Prolong Life in SMA, DMD, Physician Says

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.

John Bach

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.

Simpler Test for Anesthesia Reaction in the Works

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
Better detection of malignant hyperthermia, an adverse reaction to anesthesia, would make surgery safer for many people with neuromuscular diseases.

Wurzburg in Germany are verified.

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.

For more information about anesthesia, see "Coping with Anesthesia," Quest, 2000, no. 3. Or visit the Malignant Hyperthermia Association's Web site at www.mhaus.org, or call MHA at (607) 674-7901.

Fathers Can Pass on mtDNA

Salvatore DiMauro

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 diseases.

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
Mitochondrial DNA is usually passed from mother to child, but may occasionally be derived from the father.
from his muscle tissue, and to their surprise, the mtDNA was paternal in origin. The mutation wasn't found in the patient's father, so Schwartz and Vissing believe it may have arisen during formation of the father's sperm or shortly after conception.

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."

FDA Groups Cell and Gene Therapies

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.

Natural Chemicals Could Help Keep Hearts in Shape

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 time.

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.



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.

For research news about amyotrophic lateral sclerosis, see The MDA/ALS Newsletter or go to als.mdausa.org.



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