STUDY SUPPORTS GLUTAMATE 'POISONING' IN ALS

Glutamate, a neurotransmitter (chemical that sends signals in the nervous system) was identified several years ago as a possible source of motor neuron "poisoning" in ALS.

MDA grantee Jeffrey Rothstein at Johns Hopkins University in Baltimore has been studying glutamate and its role in ALS for about six years. In fact, Rothstein's work in this field contributed to the development of riluzole (Rilutek) and to the use of gabapentin (Neurontin), both of which partially block the action of glutamate in the brain and spinal cord and may have some protective effect on motor neurons.

Glutamate stimulates nerve cells by opening their calcium channels, letting calcium flow into the cell from the surrounding bloodstream. Too much glutamate can be toxic to cells, probably because it lets too much calcium get into them. However, until recently, it wasn't clear what was causing a surplus of glutamate in ALS, or even that there was a surplus. (There's no evidence that changing your diet with regard to glutamate or calcium has any effect on ALS.)

Last year, Rothstein's group found deficiencies of a key protein, GLT-1, in the brains and spinal cords of some patients who had died of ALS. GLT-1, or glutamate transporter 1, is a protein whose usual job is to clear away excess glutamate.

Now, Rothstein's lab reports they have identified defects in the RNA for GLT-1 in about a dozen people who died of ALS. (RNA is the next step after DNA in protein manufacture.) These patients also lacked the GLT-1 protein in their nerve cells. The research group examined 25 brain and spinal cord samples from people who died of ALS and found the defects in GLT-1 RNA and protein in about half of them.

The findings suggest that there's a genetic cause for the loss of GLT-1 in ALS and that this defect may occur in a large number of ALS patients. However, says Rothstein, the genetic defect may be the type that's acquired during a person's lifetime, rather than inherited.

Rothstein is working on methods to detect GLT-1 deficiency in living patients, a crucial step if further studies are to proceed. At this time, these transporter proteins can only be detected in samples of the brain or spinal cord, and obtaining such samples isn't possible until after death.

Further studies will also attempt to track down a culprit gene involved in GLT-1 production.

These findings support the use of riluzole and other glutamate inhibitors, Rothstein says, although he also says better, stronger glutamate inhibitors could be developed. They also support the development of other strategies to counteract excess glutamate or deficient glutamate clearance.

Return to Top

GDNF, BDNF IN THE PIPELINE

Amgen, a pharmaceutical company in Thousand Oaks, Calif., has announced a new phase 1 clinical trial of GDNF, glial-cell- derived neurotrophic factor.

The drug belongs to a group of naturally occurring chemicals shown to protect nerve cells under adverse conditions. GDNF has been found to protect nerve cells in laboratory rodents after a nerve has been cut.

The drug will be delivered directly into the fluid surrounding the brain (intraventricular delivery) via a surgically implanted access port. The company says animal evidence shows this method has the best chance for reaching motor neurons in the brain and is much more effective in preserving cells than subcutaneous (under the skin) administration.

The purpose of a phase 1 trial is to establish safety of a drug in humans. As part of the safety evaluation, Amgen will be looking at respiratory function, muscle strength and survival.

Patients will be allowed to take the FDA-approved drug riluzole (Rilutek) during the study, but investigational drugs other than GDNF will not be allowed.

Six study sites have been designated. They're in Miami, Atlanta, Rochester, N.Y., Cleveland, Madison, Wis., and Edmonton, Alberta, Canada. Very few patients will be selected at each site, since this is a phase 1 trial.

To apply to enroll in the GDNF trial, call Amgen Professional Services at (800) 772-6436.

A large, phase 3 trial of the neurotrophic factor BDNF (brain- derived neurotrophic factor) is finishing up, and data are being prepared for analysis, according to Jeanne Flynn, senior manager of professional services at Amgen. The trial was jointly sponsored by Amgen and Regeneron Pharmaceuticals of Tarrytown, N.Y. The last patient finished the nine-month trial in September, 1996.

The BDNF trial, in which the drug was administered subcutaneously, included 1,135 patients at 38 sites, 29 of which are MDA clinics. Each patient was treated with either BDNF or a placebo.

Results of the trial are expected by April, at which time the company will decide whether to seek approval for BDNF from the FDA.

For updated information about the GDNF and BDNF studies, you can call Amgen at (800) 772-6436. This is their information line for doctors, patients and all other interested parties.

Return to Top

MYOTROPHIN NOW AVAILABLE BY RANDOM SELECTION

The drug Myotrophin, developed by Cephalon (West Chester, Pa.) and Chiron (Emeryville, Calif.), is now available to a very limited number of ALS patients through a random selection program (also called an expanded access program) approved by the Food and Drug Administration (FDA) in June.

Myotrophin is the companies' brand name for the neurotrophic factor insulin-like growth factor 1.

Two large-scale clinical trials, one in Europe and one in North America, convinced the FDA to allow Cephalon to begin offering the drug. (Six of the eight North American trial sites were MDA clinics.) The European trial results raised doubts in the minds of some analysts about the drug's safety.

Full FDA approval requires the drug companies to submit a New Drug Application, or NDA. The FDA may be waiting to see the results of the expanded access program before approving such an application for Myotrophin. The first Myotrophin selection (similar to a lottery drawing) was held the week of Nov. 15 and the second the week of Dec. 9. The numbers selected will be in the hundreds, says Kori Beer, manager of corporate communications at Cephalon. If patients drop out of the program, their slots will be filled with new patients.

We're putting together an NDA now," Beer said. "We don't have an exact date [for submission], but we're working feverishly to do it." Beer says Cephalon is "facing limited resources" and won't be able to expand access to Myotrophin much further unless they have reason to believe the FDA will approve their NDA.

To register for the Myotrophin selection program, have your doctor call (800) 896-5855. The drug has to be injected, and training in injection technique is part of the Cephalon-sponsored program. Your doctor must be involoved.

Cephalon has discontinued an older information number, which was (800) 797-0705.

Return to Top

CAREGIVERS: YOU ARE NOT ALONE

"Whatever you feel, you are not alone."

These are the words of one caregiver, and are perhaps the most important words for a caregiver to keep in mind. Feelings of isolation, anguish, resentment, guilt, rage and helplessness are common in those caring for a family member with ALS. One feeling often leads to another. A child caring for a parent may harbor resentment when ALS changes the parent-child relationship, or when other siblings aren't equally involved in care. The child may then be overwhelmed by guilt at what seem like selfish emotions. A husband may feel helpless watching the progression of the disease in his wife, and at the same time unappreciated for all he's doing. Unwilling or unable to discuss his own feelings with his wife, he may become isolated and depressed. Denial of these feelings makes them worse, and the isolation deepens.

"WHATEVER YOU FEEL, YOU ARE NOT ALONE."

Recognition of this fact is a critical step in dealing with the stress of caregiving. Caregiving is stressful; incredibly so for almost anyone who does it. It requires enormous amounts of time and emotional energy, and often the redefinition or recreation of your relationship with a loved one. Unless you're careful, this level of stress can burn you out, leaving you empty of feelings and unable to experience pleasure. By recognizing and accepting your feelings as a normal part of this stressful situation, you can avoid burnout.

In her book, "Helping Yourself Help Others", former first lady Rosalynn Carter lists some of the signs of too much stress. These include less efficiency, insomnia, frustration and easily aroused irritation, feelings of emptiness, emotional exhaustion, desire to run away, and increased use of alcohol or other drugs.

HOW CAN YOU REDUCE THE STRESS OF GIVING CARE?

First and foremost, pay attention to your own needs during your time as a caregiver. Take time to enjoy some kind of relaxing outlet: gardening, exercising, reading, or just taking a nap can all help you recharge your emotional and physical resources. Do something special for yourself. Arrange to take some time off just for you, and enjoy it without feeling guilty.

Build a caregiving team. No one person can do it all, so get family members to brainstorm on ways to share what needs to be done. Shopping, cleaning and errand running can be shared, even while you remain the primary caregiver. Reversing responsibilities, so that you can get out to do the shopping, can help keep you from feeling trapped. If that's not possible, hire someone to relieve you. One caregiver called hiring her first helper "one of the most responsible decisions of my time as caregiver. I've learned that when I'm rested, I am much more effective and my loved one is better cared for."

Practice conscious stress-reduction exercises. Meditation and relaxation exercises, perhaps guided by audiotape, can be very useful for easing anxiety and reducing stress. You don't need to take a class or burn incense to benefit from these techniques: simply sitting still and focusing on breathing deeply can be calming and rejuvenating. Get a massage or take a long, hot bath.

Join a support group for caregivers. Feelings of isolation are so common in caregivers because they are suddenly dealing with traumatic experiences and disturbing emotions unlike any they've had before. Perhaps nothing is as important for dealing with these troubling feelings as simply talking about them with others in similar situations.

MDA has a number of support groups for caregivers. Many hospitals sponsor groups for caregivers as well. While these may not be ALS-specific, the issues for caregivers are often the same regardless of the medical condition.

Some resources you might find useful:

HELPING YOURSELF HELP OTHERS: A BOOK FOR CAREGIVERS by Rosalynn Carter, 1994, Times Books.

MAINSTAY: FOR THE WELL SPOUSE OF THE CHRONICALLY ILL by Maggie Strong, 1988, Penguin Books.

HELPMATES: SUPPORT IN TIMES OF CRITICAL ILLNESS by Harry A. Cole, 1991, Westminster/John Knox Press.

Return to Top

NEW CHEMICALS TO SPEED RESEARCH

Using a new research technique, MDA-funded researcher Min Li has developed a new class of chemicals useful for the study of ALS.

Li, assistant professor of physiology and neuroscience at the Johns Hopkins School of Medicine in Baltimore, describes the technique as "in vitro evolution." By generating billions of random molecules, and then amplifying those that bind most tightly to a purified spinal cord membrane protein called the NMDA receptor, Li has developed a group of small molecules called peptides with the ability to shut down the receptor. The NMDA receptor is one type of receptor for the chemical glutamate, which plays a role in neural transmission.

While the cause of ALS is still unknown, one major hypothesis of the disease process is that overactivation of glutamate receptors triggers the death of the spinal cord neurons. Scientists hope that modifying the action of glutamate receptors will eventually lead to treatments that prevent death of the neurons.

Even if the molecules that Li has developed don't themselves become useful drugs, their development has proven the effectiveness of the in vitro evolution technique for the discovery of new types of potentially useful molecules. Li showed that his molecules act at a previously undiscovered site on the glutamate receptor, a discovery that would have been difficult with traditional drug screening approaches.

According to Li, "This method should simplify the process of screening drugs that act on the receptors. By letting experimental drugs compete with isolated peptides, scientists can readily see how well a potentially therapeutic agent is working on a targeted site. This could speed up screening dramatically, which has always been one of the slower steps in drug discovery."

Return to Top

MASSACHUSETTS GENERAL CONDUCTING ALS STUDIES

Dr. Merit Cudkowicz of the Neurology Department of Massachusetts General Hospital in Boston is looking for people with ALS for her study of biological markers of free radical toxicity. Free radicals are potentially toxic chemicals thought to be involved in motor neuron damage in ALS.

The study involves a one-time blood test, after taking a drug similar to aspirin.

Study participants can be male or female and must:

* Have a clinical diagnosis of familial or sporadic ALS

* Be 18 to 75 years old

* Be willing and able to give consent

* Be willing and able to travel to Massachusetts General Hospital once.

You can call Diane McKenna-Yasek, nurse coordinator, at (617) 726-5750, or Rosa Chieu, research coordinator, at (617) 724-8420, to apply to enter the biologic marker study.

Cudkowicz says her recent trial of the drug procysteine, an antioxidant, has not been canceled, as previously announced, but rather postponed. Procysteine is converted to cysteine in the body, which is in turn converted to glutathione, a substance that detoxifies free radicals.

A phase 1 study has shown that the drug is safe and that it enters the spinal fluid. It probably enters the brain also, Cudkowicz says, but it wasn't possible to check this.

A phase 2 study will begin if and when the researchers receive funding from the Food and Drug Administration's Orphan Drug program. Cudkowicz says this funding, if approved, will come in July 1997.

Dr. Robert Miller, director of MDA's ALS Center at California Pacific Medical Center in San Francisco, will open a second branch of the procysteine study if the phase 2 study is funded.

An earlier trial of antioxidants, including vitamins, at Massachusetts General Hospital wasn't completed because the study required patients to give up taking vitamins. Too few patients were willing to be part of the study, so the results weren't considered meaningful, Cudkowicz says.

Cudkowicz has also been studying the drug penicillamine (Cuprimine, Depen) in familial ALS. The trial is a small one (only eight patients), and she's not recruiting more for now. No major effects have been seen, but the drug has generally been well tolerated. The drug, which binds copper, is usually used for Wilson's disease (a disorder involving excess copper) and rheumatoid arthritis.

Return to Top

PUBLICATION ON NECK WEAKNESS AVAILABLE

As part of their ongoing efforts to provide practical information about ALS, health professionals at the MDA ALS Research and Clinical Center at Baylor College of Medicine in Houston have created a new brochure, "Managing Neck Weakness in ALS Patients."

The publication discusses the importance of maintaining proper posture and making sure you have the correct seating system to minimize neck weakness in ALS. It also illustrates and discusses several kinds of neck support devices that are available.

"Managing Neck Weakness in ALS Patients" is free, and you can get a copy by writing to MDA/ALS Clinic, Department of Neurology, 6501 Fannin St., NB302, Houston, TX 77030.

For more information on materials available from the MDA/ALS Center in Houston, contact the center's web site at:

www.bcm.tmc.edu/neurol/struct/als/als1.html

Also see the list of publications below.

The Baylor center is one of 11 multidisciplinary MDA centers across the country devoted exclusively to ALS research and medical care.

Return to Top

The Association welcomes gifts for ALS research honoring significant occasions of achievement. These gifts may be made in tribute to special people or to mark such events as anniversaries, birthdays, weddings, graduations or retirements.

THE ALS NEWSLETTER
Muscular Dystrophy Association
National Headquarters
3300 East Sunrise Drive
Tucson, Arizona 85718-3208

Return to Issues Index