ALBUTEROL HELPS IN FSHD, MAY LEAD TO OTHER DRUGS

An MDA-supported pilot trial of the drug albuterol (Proventil) at the University of Rochester (N.Y.) Medical Center and the Ohio State University Medical Center in Columbus suggests this medication or others like it might be useful in facioscapulohumeral dystrophy (FSHD) and possibly other forms of muscular dystrophy.

The study is reported in the May issue of the journal Neurology. On average, patients showed a 12 percent gain in muscle strength when tested with standardized measurements and gained a mean of 2.83 pounds of lean body mass (composed mainly of muscle) over three months while taking 16 milligrams a day of sustained-release oral albuterol. There were 15 patients in this unblinded trial (no control group was studied), which has now been expanded at both centers.

MDA grantee John Kissel, a neurologist who co-directs the MDA clinic at Ohio State, coordinated the two-center pilot trial with Rabi Tawil, an MDA clinic co-director at the University of Rochester. He said he thinks "albuterol is worth looking at, even if it does not eventually become a standard treatment for muscular dystrophy." The drug is known as a beta receptor agonist and acts on many tissues. It's on the market as a treatment for asthma and other lung conditions.

"It's a new direction," said Kissel, adding that you don't always have to know exactly how a drug works or have a drug that works on the specific, underlying disease mechanism to help patients. "Beta receptor agonists and other anabolic agents may become very important in treating muscle diseases in the future," he said. Anabolic agents, which include testosterone-like hormones, growth hormones and beta receptor agonists, might help flawed muscle tissue rebuild itself despite the presence of a genetically caused defect, while more specific treatments that target those defects are in development, Kissel noted.

"The fundamental problem is that the muscle is still flawed," he said, "and that has to be addressed. But these agents may give a margin of safety when there's a defect that increases loss of muscle."

If you have FSHD and would like to participate in an albuterol trial, call Lynn Cos at the University of Rochester at (716) 275-7680, or Karen Downing or Cheryl Kacvinsky at Ohio State at (614) 292-1234.

LGMD GENE THERAPY SUCCEEDS IN HAMSTER

Effective gene therapy for one form of limb-girdle muscular dystrophy (LGMD) has been accomplished in a hamster model of the disorder. The research team was headed by Kevin Campbell, an MDA grantee in the University of Iowa's Department of Physiology and Biophysics.

This type of hamster has LGMD because it's missing a muscle membrane protein known as delta sarcoglycan. The protein loss is due to a genetic mutation. The disorder has a human counterpart, known as LGMD type 2F, a disorder characterized by gradual weakness of skeletal muscles beginning in the shoulders and pelvic area. Mutations in any of the four sarcoglycan genes lead to loss of all the sarcoglycan proteins at the muscle cell membrane, probably because, when one protein is lost, the others can't assemble properly at the membrane. Without these proteins, the membrane doesn't do its job of keeping certain substances in, and others out of, the muscle cell.

The researchers inserted a gene for the delta sarcoglycan protein into an adenovirus and then injected the adenovirus into a leg muscle in the hamsters. The gene produced the protein for at least six months, the researchers say. They found good evidence that the entire complex of proteins, with all the sarcoglycans, was restored at the muscle cell membrane, and that the functions of the membrane were also restored.

The researchers saw no immunologic rejection of the new protein, although there was some inflammation two weeks after the injections. They say a possible reason for this good news could be the cell's continued production of gamma sarcoglycan, a very similar protein. (Even though gamma sarcoglycan doesn't insert itself into the membrane when delta sarcoglycan is missing, it's still available for the cell to recognize as "friendly.")

The researchers also suggest that the hamsters may make fragments of delta sarcoglycan, enough to allow the body to accept the new delta sarcoglycan as its own. Such findings bode well for the human body's acceptance of LGMD gene therapy.

Campbell also points out that the sarcoglycan genes are small and fit easily inside an adenovirus, which is a good "shuttle" for gene delivery.

He emphasizes that the hamsters were not born with the new genes, as animals have been in many other experiments. "This is a postnatal gene therapy model," he said. "It shows that you can prevent degeneration of muscle, even after birth."

Campbell said the method "would probably apply to any of the four sarcoglycans involved in limb-girdle dystrophy, not just LGMD2F."

The biggest stumbling block, he said, "is trying to do this at a level that would functionally benefit the whole animal, not just a single leg muscle. That's something we're now trying to do in mice and hamsters." The study is published in the May issue of Molecular Cell.

MILDER FA ASSOCIATED WITH SMALL GENE DEFECTS IN NERVE TISSUE

Small genetic defects probably cause less severe disease than large ones in Friedreich's ataxia (FA), say MDA grantees at Baylor College of Medicine in Houston.

MDA grantees Pragna Patel and Sanjay Bidichandani, both at Baylor, were part of a research team that recently published an illustration of this likely principle as a "Case of the Month" in the March issue of Muscle & Nerve.

The researchers describe a 21-year-old woman with a genetic defect of the type known as a GAA triplet repeat in both chromosome 9 genes that code for the protein known as frataxin. A lack of the frataxin protein results in FA. While severe FA involves progressive loss of coordination, difficulty speaking and walking, heart problems and diabetes, the patient at Baylor had only mild difficulty walking and keeping her balance.

A biopsy revealed small GAA triplet repeats in nerve tissue taken from her calf, while blood tests revealed significantly larger GAA triplet repeats in blood cells.

The authors, who also include Yadollah Harati and Hazem Machkas at Baylor, speculate that a small GAA repeat also exists in this patient's central nervous system, as in her calf nerve tissue, and that her disorder is relatively mild as a result.

The larger repeats in the blood cells apparently don't cause any problems but illustrate that genetic defects of this type aren't necessarily the same in all cells. In triplet repeat disorders, the size of the defect may change as the person grows, and blood-cell DNA can't be relied upon in every patient for accurate genetic testing and prediction of disease course, as it usually can be in other types of genetic disorders.

NEW DIRECTIONS IN MITOCHONDRIAL DISORDERS

Defects in the energy-producing units of cells known as mitochondria have been known for some years to cause a wide range of disorders known as mitochondrial myopathies or mitochondrial encephalomyopathies. Mitochondria have their own DNA and are also influenced by DNA in the cell's nucleus, so defects in either type of DNA can affect their vital functions.

Understanding of such disorders was scant until recently. Now, MDA grantees Salvatore DiMauro and Eric Schon, both in the Neurology Department at New York's Columbia University, have worked out many of the steps involved in these disorders and have some ideas on how they might be treated. Their report is in the January issue of The Neuroscientist.

Flaws in mitochondrial DNA can be corrected in laboratory dishes by blocking abnormal DNA with so-called peptide nucleic acids, DiMauro says. A missing or defective protein can be supplied to mitochondria by adding a gene for that protein to the cell's nucleus, after changing the gene slightly so that it tells the cell to produce a mitochondrial protein. This, too, has been accomplished in the lab.

However, DiMauro emphasizes that both strategies depend first on getting the peptide nucleic acid or the new gene into the affected tissue, not a problem in a lab dish but a major hurdle when the target tissue is nerve or muscle inside the body.

Mitochondrial disorders are now sometimes treated with substances that seem to compensate for the loss of some energy production functions. These substances include coenzyme Q10, carnitine, vitamins C and K, and various components of the vitamin B complex, especially riboflavin.

Even a little help can mean a lot in mitochondrial disorders, says DiMauro, a neurologist. "Patients can be sick when they have 85 percent mutant mitochondria in a given tissue but, if they have 80 percent, they may be much, much better and may not show symptoms. So, if you can change the proportions even slightly, you may do the patient a lot of good."

Schon, a molecular biologist, is working on developing the first animal models of mitochondrial encephalomyopathies, in which treatment strategies can be tested.

BONE MARROW CELLS CAN MAKE NEW MUSCLE

Cells that originate in bone marrow and circulate in blood can travel to damaged muscle and repair it, say scientists in Italy who published their findings in the March 6 issue of the journal Science. Their work is based in part on findings by Arnold Caplan of Case Western Reserve University in Cleveland. In 1996, Caplan, with MDA funding, identified bone-marrow-derived stem cells that are apparently capable of forming muscle when needed to do so.

The findings of the Italian group have at least three possible therapeutic implications, says Caplan, a biologist who directs the Skeletal Research Center at Case Western Reserve. First, he says, people with muscular dystrophy might benefit from receiving donated bone marrow cells from close relatives who don't have any muscle disorder. Such cells would carry a full complement of muscle protein genes, including those lacking in someone with muscular dystrophy. This type of strategy is already being tried in children with a genetic bone disorder, Caplan notes.

Caplan says another possibility to pursue is using a patient's own bone marrow cells, engineered to carry a new gene, to compensate for any abnormal gene leading to muscular dystrophy. For example, children with Duchenne muscular dystrophy could have bone marrow cells extracted (normally done from the hip bone, using a large needle), engineered to carry a dystrophin gene in the laboratory, and then reinserted. Bone marrow cells can be reinserted by injecting them into the bloodstream; they don't have to be reinjected into bone.

A third possibility, and perhaps the most practical for the near future, would be to increase production of bone marrow cells that can become muscle without changing their genetic makeup. Since boys with Duchenne generally walk until they're at least 7 or 8 years old, many researchers have speculated that, until this age, muscle regeneration outpaces degeneration despite the presence of an abnormal dystrophin gene. (A similar process probably occurs in other forms of muscular dystrophy, where the onset of severe weakness sometimes arrives after childhood, despite an abnormal gene's presence since birth.)

If it were possible to increase muscle regeneration, even if the genetic defect remained in place, you might significantly tip the balance toward muscle strength and preservation instead of muscle destruction and weakness, Caplan says.

STUDY ON MYOTONIC DYSTROPHY OPEN AT ROCHESTER

Neurologist and MDA research grantee Richard Moxley at the University of Rochester (N.Y.) Medical Center is doing a study on the causes of the metabolic abnormalities and muscle wasting seen in myotonic muscular dystrophy (MMD). The study will compare findings in people with myotonic dystrophy to findings in three other groups -- people with other neuromuscular disorders, people with insulin resistance and people without any disorders. The researchers hope to identify specific alterations in body function that could eventually lead to new therapies.

They're looking for participants with myotonic muscular dystrophy, facio-scapulohumeral muscular dystrophy, Charcot-Marie-Tooth disease, or insulin resistance, and without any disorder. Participants must be between 21 and 60 years old, must not be obese and must be able to walk.

The study requires three inpatient stays at the University of Rochester General Clinical Research Center. The first stay is five days, and the second and third are each three days.

Call nurse Cheryl Barbieri at (716) 275-5409 or send her an E-mail at research@mail.neurology.rochester.edu for information.