FUNCTION OF SMN PROTEIN REVEALED IN SMA STUDY

Ever since mutations in the SMN (survival of motor neurons) gene were linked to spinal muscular atrophy (SMA), a disease that affects the motor neurons of the spinal cord, researchers have been trying to understand what the protein produced by this gene normally does in the cell, and how mutations in this protein cause motor neuron loss. Now, a groundbreaking study from Gideon Dreyfuss of the Howard Hughes Medical Institute at the University of Pennsylvania in Philadelphia answers some of these questions.

Previous studies by Dreyfuss (Quest Vol. 5, no. 5, and Vol. 6, no. 1) have indicated that the SMN protein may be involved in the processing of RNA molecules, the intermediate messengers that use information from DNA to instruct the production of proteins. However, it wasn't known exactly how SMN was involved in RNA processing.

Dreyfuss recently took this work a step further by determining that the function of the SMN protein is to stimulate RNA processing in cells, and by describing how it does this.

Spliceosomes are groups of proteins that turn pre-RNA into mature RNA by removing information not required for protein production. SMN makes this process more efficient by helping the spliceosome proteins stay together.	Without SMN, the proteins that form the spliceosome don't stay assembled between rounds of splicing and so must be reassembled each time. This slows the production of proteins.

Specifically, Dreyfuss found that the normal SMN protein increases the efficiency of a process known as RNA "splicing," in which a group of proteins called a "spliceosome" takes out irrelevant information in the RNA strand and splices the ends back together. SMN does this by helping the proteins of the spliceosome complex stay assembled, and by helping them reassemble if they come apart.

It seems that proper RNA splicing might be very important in motor neurons because motor neurons normally have high concentrations of both spliceosomes and the SMN protein. Dreyfuss' findings predict that the motor neuron abnormalities that characterize SMA may occur because a decrease in the amount of the SMN protein leads to a decrease in the efficiency of RNA splicing. Defective RNA splicing may then lead to an inability of the motor neurons to produce proteins vital for their survival.

"In terms of therapy," Dreyfuss says, "I think these findings open up a very important avenue to look for potential therapeutics because we now have a specific biochemical activity for the protein -- an activity that we can carry out in the test tube. We can therefore use this activity as an assay [test] to search for compounds that can carry out this function. In other words, that can either substitute for, or enhance, the activity of the SMN protein."

IGF-1 MAY KEEP MUSCLES STRONGER LONGER

New anti-aging research may lead to gene therapies that jump-start the natural repair system in muscles, thus slowing the muscle degeneration that occurs in muscular dystrophy and other neuromuscular disorders.

Between the ages of 30 and 80, during the normal aging process, up to one-third of the original size and strength of the body's muscles may be lost. Researchers think that this gradual deterioration with age occurs because the muscles of older people lose their natural ability to repair damage accumulated through daily wear-and-tear.

Some scientists think that the gradual loss of muscle strength during aging mirrors, at a slower rate, that which occurs in degenerative muscle diseases such as muscular dystrophy. The muscles of people with muscular dystrophy also have a natural ability to repair themselves but, because the muscle cell membrane is very fragile, muscle damage accumulates more quickly than the body's repair system is able to handle it.

A team of researchers, including MDA grantees H. Lee Sweeney of the Department of Physiology at the University of Pennsylvania, and Antonio Musaro of the Cardiovascular Research Center of Massachusetts General Hospital in Boston, has managed to prevent the age-related loss of muscle size and strength in older mice by injecting the muscles of the mice with a virus containing the gene for insulin-like growth factor 1 (IGF-1).

IGF-1 is a substance normally found in the body and is thought to participate in the muscle repair system by stimulating cell division.

Young adult mice that received the IGF-1 treatment showed a 15 percent gain in muscle strength, while older mice that received the IGF-1 treatment showed no loss of muscle strength or size. Older mice normally lose 15 percent of their muscle strength.

One possible application for the IGF-1 treatment is to help repair muscle damage accumulated in degenerative muscle disorders.

"I think the diseases where you might really see a major effect," Sweeney says, "are in the milder dystrophies, such as Becker." Sweeney points out that this approach could be tried in all of the primary muscular dystrophies, and even in diseases such as amyotrophic lateral sclerosis (ALS), where muscle degeneration is a secondary effect.

It's unclear at this point whether the IGF-1 treatment will be as effective in preventing muscle loss in diseases as it is in preventing age-related muscle loss. Sweeney has begun a study of the effects of IGF-1 in mice that lack the gene for dystrophin.

"So far, we've seen some short-term benefits in the dystrophic mice," Sweeney says, "but, unfortunately, these effects wear off."

PEOPLE WITH PM OR DM NEEDED FOR FDA STUDY

The Laboratory of Molecular and Developmental Immunology of the Food and Drug Administration is conducting a study of the potential relationship between immunizations (vaccinations) and myositis, a disease characterized by inflammation of the muscle.

The investigators are interested in studying people who received any type of vaccine and then developed any form of myositis (including polymyositis and dermatomyositis) within six months. They are also studying subjects who received the same vaccine and are well.

Enrollment consists of completion of a questionnaire and donation of a blood sample through a local physician.

For further information, please contact:

Dr. Ejaz Shamim or Dr. Frederick W. Miller
Laboratory of Molecular and Developmental Immunology, CBER, FDA
Building 29B, Room 2G11, HFM-561
Bethesda, MD 20892
Phone: (301) 827-0459 or (301) 827-0659
Fax: (301) 827-0852
E-mail: shamim@cber.fda.gov or millerf@cber.fda.gov

LGMD GENE THERAPY ENROLLMENT UNDER WAY

The pre-trial screening process for MDA-sponsored gene therapy for limb-girdle muscular dystrophy (LGMD) has begun. Researchers anticipate that the first phase of the trial will begin in late March pending approval from the Food and Drug Administration (FDA).

This first phase of the clinical trial, phase l, is designed to test the safety and feasibility of putting viral vectors (delivery vehicles), each carrying a functional copy of one of four sarcoglycan genes, directly into the muscles of people with LGMD.

MDA's LGMD gene therapy working group, consisting of 20 physicians, scientists and clinical trial evaluators, met recently to establish guidelines for the development of a patient registry for this and other trials. The meeting was chaired by Jerry Mendell, neurologist and MDA gene therapy project director at Ohio State University in Columbus.

Because there are many genetic mutations that can lead to LGMD, applicants will undergo genetic testing to determine if their symptoms are due to defects in one of the four sarcoglycan genes (alpha, beta, delta and gamma) being tested in the trial. About one-third of all cases of LGMD are due to mutations in one of these genes. Those at least 16 years old will be given priority because of safety concerns, but younger participants may be considered.

During the trial, a re-engineered virus carrying the appropriate sarcoglycan gene will be injected into the extensor digitorum brevis muscle of one foot, and saline (a salt/water solution) will be injected into the same muscle of the other foot. Participants will then be closely monitored over a period of four months for adverse reactions to the viral vector and sarcoglycan genes. Researchers will also try to determine if sarcoglycan genes have been successfully transferred to the cells of the injected muscle.

Investigators from seven medical centers are participating in the LGMD study group. The centers are: the University of Pennsylvania in Philadelphia, Ohio State University, the University of Iowa in Iowa City, Children's Hospital of Boston, Washington University in St. Louis, Vanderbilt University in Nashville, Tenn., and the University of Rochester (N.Y.). The initial clinical trials will take place at Ohio State University and the University of Pennsylvania.

MDA grantee James Wilson, head of the University of Pennsylvania's Institute for Human Gene Therapy, has been instrumental in the development of the viral delivery vehicles for each of the sarcoglycan genes. Wilson plans to begin the trials soon after final FDA approval.

Applications for the LGMD gene therapy trial are now being accepted. You can fill out and submit an application on the MDA Web site , or obtain an application by calling MDA at (800) 572-1717.