QUEST Volume 11, Number 3, MAY/JUNE 2004

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Key Finding in SBMA Suggests Therapy

Lisa Ellerby

MDA grantees Albert La Spada and Lisa Ellerby were part of a team that recently uncovered a key factor in the degeneration of motor neurons (muscle-controlling nerve cells) in spinal-bulbar muscular atrophy (SBMA). Their work also suggests a possible pathway to therapy for this late-onset, slowly paralyzing disease.

Albert La Spada

La Spada works in the University of Washingtons Departments of Laboratory Medicine and Medicine-Medical Genetics in Seattle; Ellerby is a molecular biologist at the Buck Institute in Novato, Calif.

The investigators, who published their work in the March 4 issue of the journal Neuron, found that the key factor in the loss of motor neurons is likely to be the partial loss of a protein called vascular endothelial growth factor (VEGF). This VEGF diminution appears to be a far downstream result of the primary genetic problem in SBMA, the researchers said.

La Spada was part of the original research team that in 1991 identified the primary genetic defect in SBMA, noting it to be a flaw in the androgen receptor, a molecular ferry that takes male hormone molecules from the bloodstream into cells. Once inside a cell, these hormones stick to specific DNA in the nucleus and cause changes in protein production. If the receptor is flawed, its actions and those of the hormones in the nucleus may be abnormal as well.

The new study shows that the abnormal androgen receptor results in lowered VEGF production.

Loss of VEGF via a different mechanism (variations in the VEGF gene itself) has also recently been implicated in the development of another motor neuron disease, amyotrophic lateral sclerosis (ALS), and this finding suggests the loss of sufficient VEGF may link the two diseases.

The next step, La Spada and colleagues say, will be to see whether mice with ALS or SBMA do better when given VEGF.

In normal motor neurons (above), androgen molecules enter the cell and stick to androgen receptors inside. They're then ferried to the cell's nucleus, where the stick to a specific section of DNA. Normal motor neurons produce plenty of VEGF. In SBMA-affected motor neurons (below), the androgen receptors are abnormal. The current study shows that at least one important result of this abnormality is a diminished production of VEGF.

Researchers Combine Stem Cells, Gene Therapy to Treat Mice With DMD

Louis Kunkel

A team that included MDA-supported researchers Louis Kunkel at Harvard Medical School in Boston and Jeffrey Chamberlain and Sheng Li at the University of Washington in Seattle announced in the March 9 issue of Proceedings of the National Academy of Sciences that theyve combined stem cell and gene therapies to successfully treat mice with Duchenne muscular dystrophy (DMD). Estanislao Bachrach (Harvard) was also a major contributor to the research.

Jeffrey Chamberlain

The mice were treated with a type of muscle-derived stem cells known as SP (side population) cells that had been given genes for human dystrophin, the protein needed in DMD. The cells came from mouse muscles, but researchers believe this type of cell likely exists in humans.

The investigators injected the cells into mouse tail veins and then observed them migrate through the circulatory system. They homed in on damaged muscle areas in the DMD-affected animals, where they produced human dystrophin in a small but measurable number of muscle fibers.

The mouse studies pave the way for using genetically corrected stem cells from patients own muscles (autologous transplants) to treat muscle diseases.

CLINICAL TRIALS AND STUDIES

Genzyme Expands Pompes Program

Genzyme, a biotechnology company based in Cambridge, Mass., has expanded its program in acid maltase deficiency (AMD, Pompes disease).

The companys patented enzyme, Myozyme, is designed to compensate for a deficiency of the acid maltase enzyme in the disease. MDA-supported basic research contributed substantially to the development of Myozyme, which is now being tested in young children in two clinical trials.

In addition to these ongoing trials, the company offers an "expanded access" program to allow infantile-onset and late-onset Pompes patients access to Myozyme if theyre not eligible for the formal clinical trials because of advanced disease or other factors.

The program is now taking applications for enrollment.

In addition, an observational study (not involving any treatment) of late-onset Pompes, diagnosed in people age 8 or older, is also open through Genzyme. Some participants in the observational study, to be conducted largely through MDA clinics, will be invited to take part in a later trial of the experimental enzyme.

The company also invites anyone with Pompes to enroll in a disease registry that will help investigators study the natural progression of the disorder and design future clinical trials of potential treatments for it. A doctor has to fill out the registry forms, but families can contact Genzyme to start the process.

For participation criteria for these studies or to see about receiving Myozyme, go to MDAs clinical trials listing on the Internet (www.mda.org/research/ctrials.aspx), or visit Genzymes site at www.pompe.com. You can contact Genzyme at (800) 745-4447, (617) 768-9000 or medinfo@genzyme.com.

Albuterol Improves Strength in DMD, BMD

An MDA-supported pilot study of the drug albuterol in Duchenne muscular dystrophy (DMD) and its less severe variant, Becker MD (BMD), conducted at the University of California at Los Angeles, has shown encouraging results.

Melissa Spencer

MDA research grantee Melissa Spencer, a muscle biologist at UCLA, with neurologist Michael Graves, who co-directs the MDA clinic at that institution, were part of the research team, which published its results in the March 23 issue of Neurology.

Nine boys ages 5 to 9, all of whom were still walking, took part in the trial, which showed that muscle strength increased with albuterol treatment compared to treatment with a placebo (inert substance). Strength particularly increased in the thigh muscles.

Some muscles didnt show improvement, and the researchers say they think uptake of albuterol may vary in different muscles. Timed function tests (such as climbing four stairs or walking 30 feet) didnt improve. There were no apparent side effects.

The researchers are conducting a larger trial to confirm the safety and effectiveness of this drug. For information, call (310) 794-5225; or e-mail mspencer@mednet.ucla.net.

Meanwhile, other drugs in the same class as albuterol, such as fenoterol, are being studied in rodents. MDA grantee Gordon Lynch at the University of Melbourne in Victoria, Australia, is conducting those studies.

Blood Pressure Med to Be Studied in FSHD

Diltiazem, a medication usually used to treat high blood pressure and certain cardiac conditions, is being tested at Ohio State University Medical Center in Columbus to see if it can improve strength in facioscapulohumeral muscular dystrophy (FSHD). Diltiazem may reduce the entry of potentially damaging calcium into muscle cells.

This MDA-supported study seeks 20 people with FSHD who are between 18 and 60 years old; dont require a wheelchair but have weakness of certain facial muscles and muscles of the shoulder area or foot; have at least one member of the family who has had a positive DNA test for FSHD; and meet other study requirements. Neurologist Gloria Galloway is overseeing the trial.

For more information, contact Karen Downing, study coordinator, at (614) 292-1156.

Neurotrophic Factor Eyed in CMT Treatment

Zarife Sahenk

Zarife Sahenk, a neurologist at Ohio State University in Columbus who has received MDA funding to study cellular mechanisms in Charcot-Marie-Tooth disease (CMT), has found that the natural substance neurotrophin-3 (NT3) may be useful in treating the disease.

NT3 is one of several "neurotrophic" (nerve-nourishing) substances found in the body. The NT3 in the trial was supplied by Regeneron Pharmaceuticals.

Sahenk studied eight people with CMT type 1A, which impairs maintenance of the myelin covering of the peripheral nerves. Myelin normally helps these nerves carry motor signals from the spinal cord to the muscles and sensory signals back to the spinal cord.

At the end of the six-month trial, during which patients injected themselves with either NT3 or a placebo three times a week, the investigators found that those on NT3 had more myelinated nerve fibers in the examined area. They also performed better on tests of pinprick, vibration and temperature sensitivity, compared to patients on the placebo.

NT3 treatment was thought by the investigators to have promoted nerve regeneration, at least in the examined sural nerve, located in the lower leg.

"We are committed to taking this to the next step," Sahenk said. "That will require multicenter trials to test NT3."

Long-Term Idebenone Looks Promising in Friedreichs

Idebenone, a compound similar to coenzyme Q10, continues to show promise in treating the heart complications of Friedreichs ataxia (FA), notes correspondence published in the Feb. 10 issue of Neurology.

Researchers had previously reported (see "Research Updates," July-August 2003) significant benefits for the FA-affected heart after short-term treatment with the compound, which has been approved for use by European regulators but not by the U.S. Food and Drug Administration.

Kenneth Fishbeck

The new report says that a French patient who took 5 milligrams per kilogram of body weight of idebenone per day for five years had significant reduction of abnormal heart enlargement and complete resolution of heart dysfunction. Cardiac enzymes were largely restored to normal. The researchers describe the drug as having had a "spectacular effect."

Idebenone is being tested at the National Institutes of Health in Bethesda, Md., under the direction of neurologist Kenneth Fischbeck.

"A dose-escalation tolerability study is nearing completion, and a longer-term trial of high-dose treatment is planned," Fischbeck said. "The hope is that high-dose treatment will prove to be safe and may be more effective than the doses used in other studies to date."

For information, call (800) 411-1222, or e-mail prpl@mail.cc.nih.gov.