GENE THERAPY ADVANCES

A major advance in the quest for gene therapy for muscular dystrophy occurred in June, when MDA grantees Jeffrey Chamberlain at the University of Michigan and Paula Clemens at the University of Pittsburgh announced that their groups had successfully stripped an adenovirus of all its own genes. Former MDA grantee C. Thomas Caskey, now at Merck Laboratories in West Point, Pa., and formerly at Baylor College of Medicine in Houston, also contributed to the studies.

Adenoviruses are the preferred vehicle (vector) for carrying therapeutic genes to muscles. Until now, an immune response to the adenovirus has been an obstacle to gene therapy. Researchers are hoping that the immune response to the hollowed-out virus will be lessened or non-existent.

The hollow virus also allows the insertion of a large gene capable of making a full-length dystrophin protein. This is the protein that's missing in Duchenne dystrophy and altered in Becker dystrophy. Previous adenoviral vehicles could carry only a partial dystrophin gene (a minigene), capable of making shortened versions of the dystrophin protein that are not quite as effective as that made by the full gene.

Studies in mice are under way that will show whether there is an immune response and whether the full-length protein lasts.

DMD, BMD CARRIERS OFTEN HAVE HEART PROBLEMS

An Italian study shows that heart problems are very common in female carriers of Duchenne and Becker muscular dystrophies.

The researchers studied 197 women and girls ages 5 to 60 who were known carriers of DMD or BMD. Heart involvement was found in 166 (84.3 percent), with no significant differences between carriers of DMD versus BMD. In carriers between ages 5 and 16, 54.5 percent had cardiac problems; in carriers older than 16, 90.2 percent showed heart involvement. Some of the heart problems were not severe, but the investigators found the abnormalities progressed over time.

The researchers advise cardiac evaluations for female relatives of boys and men with DMD and BMD.

STOPPING MUSCLE LOSS FOCUS OF MEETING

On June 7 and 8 (1996), MDA brought to Tucson some 50 scientists and doctors from around the world to present their ideas for combating Duchenne dystrophy and related disorders while gene therapy is being developed.

Participants agreed that lack of dystrophin protein, a vital part of a group of proteins clustered at the muscle cell (fiber) membrane, probably causes a cascade of muscle-destroying events in Duchenne, some of which might be stopped even if dystrophin isn't replaced.

Without dystrophin, the protein clusters that normally line the periphery of muscle fibers don't form. (Mature muscle cells are called fibers.) As a result, the scientists believe, substances that are supposed to stay outside the fibers probably leak in.

Some of these substances may set off a chain of events that ultimately leads to the death of the fiber.

Some scientists proposed that there may also be substances that leak out of the cell and send a "wounding signal" to the surrounding area, recruiting substances that cause inflammation and scarring.

The immune system may be involved in destruction of muscle fibers that appear damaged.

Possible methods of blocking various paths of destruction were discussed.

Richard Moxley of the University of Rochester (N.Y.) and Gerald Fenichel of Vanderbilt University presented recent studies of the corticosteroids prednisone and deflazacort in the treatment of Duchenne (see related story). Moxley is strongly convinced that these drugs slow the progression of the disease and delay the need for wheelchairs and ventilatory assistance, sometimes by several years. The drawback is that they can have severe side effects. For this reason, many doctors and patients are reluctant to use them on a long-term basis.

The mechanism by which these drugs work in Duchenne isn't well understood, and participants suggested that it be studied. Researchers would like to duplicate the desired effects of corticosteroids with fewer unwanted effects.

Another family of drugs, known as beta receptor agonists, is also getting attention. John Kissel at Ohio State University in Columbus has MDA funding to start a full-scale trial of albuterol, a beta receptor agonist, in facioscapulohumeral dystrophy. A recent small pilot study of albuterol in FSHD showed promise.

MDA-funded researcher Joseph Etlinger at New York Medical College in Valhalla is studying another beta receptor agonist, clenbuterol, in mdx mice, which have a Duchenne-like disease.

These drugs seem to increase the amount of muscle by changing muscle cell biochemistry. The exact mechanisms aren't understood.

FDA OKS EARLY ACCESS FOR MYOTROPHIN

On June 24 (1996), the Food and Drug Administration approved an early access program for the new drug Myotrophin for amyotrophic lateral sclerosis patients.

The drug companies Cephalon (West Chester, Pa.) and Chiron (Emeryville, Calif.) will soon begin distributing limited amounts of Myotrophin through a computerized, random selection program. The companies also plan to submit an application for full approval of the drug this summer.

Myotrophin is based on the natural substance insulin-like growth factor 1, one of a group of neurotrophic (nerve-nourishing) factors identified in the last decade. Neurotrophic factors seem to protect nerve cells from damage under a number of conditions. MDA has long supported research in these substances, and clinical trials were conducted at MDA-supported clinics.

For updated information about Myotrophin and the early access program, call Cephalon's information line at (800) 797-0705.

NEW SYSTEM DELIVERS ALS DRUG TO BRAIN, SPINAL CORD

The biotechnology company Cyto-Therapeutics (Providence, R.I.) is testing a unique system to deliver drugs to the central nervous system (brain and spinal cord) in 10 patients with amyotrophic lateral sclerosis.

The trial involves inserting a capsule that contains cells that produce CNTF, a neurotrophic (nerve-nourishing) factor that might be beneficial in ALS if it could be delivered directly to nerve cells and diverted from other tissues. The cell-containing capsule is inserted at the base of the spinal cord, where it leaks CNTF into the spinal fluid.

NEW PENICILLAMINE TRIAL IN FAMILIAL ALS

Researchers at Massachusetts General Hospital in Boston are recruiting patients with familial amyotrophic lateral sclerosis for a trial of the drug penicillamine, which may block the effects of an abnormal superoxide dismutase 1 protein produced in this condition.

Patients must have a clinical diagnosis of familial (genetic) ALS, be between 18 and 75 years old, and be willing and able to give informed consent. The drug will be given orally for about six months. Call Rosa Chiu at (617) 724-1873.

The Massachusetts General researchers say a previously planned trial of procysteine, an antioxidant, has been canceled.

SOD1 TRIAL UNDER WAY IN ALS

MDA-funded researcher Ted Munsat at New England Medical Center in Boston has injected a normal form of superoxide dismutase 1 (SOD1) into the spinal fluid of 16 amyotrophic lateral sclerosis patients. SOD1, an antioxidant protein, is known to be defective in patients with genetic ALS. Normal SOD1 may be therapeutic in both these patients and those with non-genetic (sporadic) ALS. All patients tolerated the procedure well.

ALS DRUG RILUTEK APPROVED IN EUROPE

The ALS drug Rilutek was approved June 11 (1996) for use in the 15 countries of the European Union. It was approved by the Food and Drug Administration for use in the United States in December.

RILUTEK TRIAL PUBLICIZED IN JOURNAL

A paper published in the May 25 issue of the British medical journal The Lancet made public details of the 959-patient trial in the United States and Europe that was instrumental in convincing regulatory agencies to approve Rilutek. After 18 months of treatment with either the drug or a placebo, 50.4 percent of patients receiving placebo were still alive without tracheostomies, compared with 56.8 percent of those on Rilutek. A dose of 100 milligrams a day was determined to be the best starting dose.

RODENTS WITH CMT TO SPEED RESEARCH

Two independent research teams, both in Europe, have developed mice and rats with a genetic abnormality that causes the most common form of Charcot-Marie-Tooth disease.

In CMT type 1A, a disease of peripheral nerves, the genetic defect is a duplication of or defect in the PMP-22 gene on chromosome 17. These abnormalities affect myelin, an insulating sheath around nerves. Without normal myelin, there are difficulties in movement and sometimes sensation, particularly in the hands and feet.

Animal "models" of human diseases make it much easier to understand disease mechanisms and rapidly test potential treatments.

OVERCOMING INSULIN RESISTANCE

Since the 1960s, studies have found that the muscle cells of myotonic dystrophy (MMD) patients are not as sensitive to the hormone insulin as those of people without the disease. This resistance to insulin may in part explain the muscle wasting seen in myotonic dystrophy.

Richard Moxley at the University of Rochester is starting an MDA- supported study of a new drug, troglitazone, in myotonic dystrophy. This drug, in development by Parke-Davis (Morris Plains, N.J.) for use in diabetes, improves the action of insulin as it reaches cells. It seems to influence the way cells react to insulin rather than to affect insulin itself.

Moxley says troglitazone has almost no side effects and it can be given by mouth. The trial will show whether or not it's effective in reducing muscle wasting.

To apply for entry into this trial, call Cassandra Millard at (716) 275-1005. Applicants must have myotonic dystrophy and be 21 to 60 years old.

CORRECTION

In the last issue of Quest (Vol. 3, No. 2), it was stated that MDA grantees Massimo Pandolfo and Sanjay Bidichandani at Baylor College of Medicine in Houston "led a team" that identified a gene for Friedreich's ataxia. Although both were MDA grantees on the project, Pandolfo was the leader of the team.