May 1, 2002

On Seeing the Broader View in ALS Research

Although we have some distance to go before we can announce that we know how to stop the deadly disease amyotrophic lateral sclerosis — also known as ALS or Lou Gehrig's disease — the time has come to say we've come a long way. And I think we're going to go a lot further a lot sooner than some people believe.

When Yankees baseball player Lou Gehrig developed the disease more than 60 years ago, there were no treatments and no clues as to the cause of this paralyzing and ultimately fatal disease to which Gehrig succumbed in 1941. His devoted wife, Eleanor, fed him grass for its vitamin E content. That was about all she could do.

The causes of, and treatments for, ALS remained stubbornly elusive. But by the early 1990s, there were quite a few ideas about ALS, and most of them came from the laboratories and clinics of MDA-funded investigators.

In particular, a young physician-scientist named Jeffrey Rothstein at Johns Hopkins University in Baltimore was working on a theory that ALS could be caused by misregulation of a chemical called glutamate, one of a number of substances that send signals from one cell to another in the nervous system.

Rothstein and other MDA-supported researchers looked closely at glutamate — how it was formed, released, sent from some cells, received by others, and then whisked away after its work was done. Their findings suggested that there was too much glutamate in the area around nerve cells in people with ALS, and that flaws in the cellular processing of glutamate were likely at fault.

By the end of 1995, the pharmaceutical company Rhone-Poulenc Rorer announced that it had evidence from large-scale clinical trials that a drug that interfered with glutamate could slow the progression of the disease. That drug, Rilutek, now marketed by Aventis Pharmaceuticals, was the first ever to be approved by the U.S. Food and Drug Administration for the specific treatment of ALS. The development of this drug, which was launched to the general public early in 1996 and remains a mainstay of ALS treatment, owes a great deal to MDA-supported basic science research.

More recently, Benjamin Brooks, who directs the MDA/ALS Center at the University of Wisconsin in Madison, observed something interesting about a patient of his who had both ALS and breast cancer. Instead of the expected decline in strength and function from ALS, the patient demonstrated an actual gain in strength for a time and then a stabilization of function over the next three years. At the time, she was taking a new breast cancer drug, tamoxifen.

Building on the earlier glutamate research and leaving no stone unturned, Brooks read up on tamoxifen and found a paper suggesting it, too, might interfere with glutamate. After first testing the drug in ALS-affected mice and finding that it prolonged their survival, Brooks applied for and received MDA support to study the effects of tamoxifen in people with ALS. That study is now under way.

Meanwhile, back East, the Hopkins researchers, including Rothstein and Dan Drachman, co-directors of the MDA/ALS Center there, were thinking in yet another direction.

In the late 1990s, Drachman began seeing reports that glutamate doesn't just come from nerve cells but from other cells around them called astrocytes. Astrocytes, he learned, release glutamate in response to other body chemicals, among them one called COX-2.

That was just about the time that celecoxib, often known by the brand name Celebrex, was becoming an important anti-arthritis drug, which slowed the development of inflammation in that disorder. The new drug was known to act by blocking COX-2.

Recognizing that COX-2 blocking could probably decrease glutamate levels and that some of its other properties, such as inflammation slowing, might also help save nerve cells, Drachman set about testing celecoxib, first in laboratory dishes filled with nerve cells and then in mice with ALS. The cells and the mice lived longer than expected with the treatment. The drug is now in clinical trials with MDA support at many centers across the country.

Then, last month, MDA-supported physician-biologist Gyula Acsadi at Wayne State University in Detroit announced a triumph in an entirely different direction when he and his colleagues successfully treated mice with ALS using a gene therapy strategy. The research team inserted genes for a nerve-nourishing protein known as GDNF into the muscles of the mice, from which it likely traveled to their nerve cells, slowing the course of their disease.

These are just a few of the new avenues MDA is exploring in ALS research. We're also pursuing stem cells, programmed cell death, nerve cell killers, a possible viral cause, genetic aspects, environmental factors … and more.

To those of you who despair of ever living to see a cure or even an effective treatment for ALS, I say, "Don't give up. Where there's research, there's hope." MDA spends $3.5 million a year on ALS-related research — and we're not giving up until we get results.

With every best wish…

P.S. Keep checking the MDA ALS Division Web site to keep up-to-date on MDA's extensive ALS program, including some new elements being introduced to observe ALS Awareness Month in May.

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