Wisconsin ALS Expert Pursuing Viruses, Tamoxifen & Gulf War Exposure

by Margaret Wahl on Sat, 2002-02-16 13:20
Benjamin Brooks
Benjamin Brooks directs the MDA/ALS Center at the University of Wisconsin. The center was established in 1987.

Benjamin Rix Brooks directs the MDA/ALS Center at the University of Wisconsin Hospital & Clinics in Madison. Brooks graduated from Harvard Medical School in 1970 and completed a residency in neurology at Massachusetts General Hospital in 1974. He's now a professor of both neurology and medical microbiology and immunology at the University of Wisconsin.

Q: How did you first become interested in research on amyotrophic lateral sclerosis (ALS)?

A: My interest in ALS came out of the polio era. I had a cousin who had polio, and I took care of him in the 1950s and 1960s, when I was a kid. He was in an iron lung, which was the old-time method of respiratory support. Polio was a formative experience for people born back then. [The polio virus affects the same muscle-controlling nerve cells, the motor neurons, that are affected in ALS.]

I got interested in viruses and went to work in John Enders' laboratory at Harvard University in 1967. Enders had figured out how to grow the polio virus and got the Nobel Prize for that in the 1950s. My particular interest has been in viruses that enter the nervous system — neurotrophic viruses.

Since then, it's been found that certain viruses, at least in mice, can activate other viruses that are lying dormant in the spinal cord. Whether there are linkages among various viruses and ALS or between viruses and other factors remains to be seen.

Q: Where is the research now with respect to a possible connection between viruses and ALS?

A: Well, for one thing, we know now that there's an increased prevalence of ALS in AIDS patients. AIDS is, of course, caused by the human immunodeficiency virus, or HIV, so that's an intriguing observation with respect to viruses and ALS.

Whether there's a link between other viruses and ALS isn't known, but there's some French work and some work going on at the University of California at Irvine that suggests there is.

Q: Does treating the viral disease treat the ALS?

Benjamin Brooks
Benjamin Brooks

A: Over the last 20 years or so, there have been isolated cases of ALS in AIDS patients, and sometimes the ALS has benefited when the AIDS was successfully treated.

But the question for which many people need an answer is this: Is there a downstream effect of the HIV virus once it gets into the nervous system that's common to both the virally associated ALS and the more common, or classic, ALS, in which no known virus can usually be found? If there is, then maybe treating ALS with antiviral drugs could have benefit.

Because of the theory that you might be able to treat some downstream viral effect that's common to all forms of ALS, they're now testing one of the AIDS drugs, indinavir (Crixivan) to see if it helps in non-AIDS-related ALS. There's a study under way in New York that's going to look at this question.

Q: I know you're conducting a clinical trial of tamoxifen (Nolvadex) at your center. What brought you to the idea of using tamoxifen, which is normally thought of as a breast cancer treatment, as an ALS drug?

A: We first got interested in tamoxifen when we had a patient with ALS who developed breast cancer about the same time. She went on tamoxifen and seemed to have a very slow course with her ALS. She seemed to actually increase in strength and then stayed at about the same level of function for over three years. So, we put that observation in the backs of our minds.

Then a paper came out suggesting that tamoxifen might help protect cells from glutamate toxicity. [Excessive stimulation by the central nervous system chemical glutamate has long been suspected of damaging nerve cells in ALS.]

That's when we thought we should look at this drug in animals. A preliminary study showed tamoxifen alone prolonged survival in mice with an ALS-like disorder. We're now giving the mice tamoxifen and AIDS drugs together. The patients are just getting tamoxifen. [The mice were given a virus called ts1, which causes an AIDS-like disorder that also resembles ALS.]

We think the animals got a little bit stronger with tamoxifen, and we'll be looking for the same signs with humans.

Q: Do you think the tamoxifen is treating the viral disease caused by the ts1?

A: As with the AIDS drug speculations, we're thinking the tamoxifen may be working on something common to the virally induced ALS and also the classic ALS — something "downstream" from where the virus enters the nervous system.

Q: What do you think tamoxifen is doing in the motor neurons — in the mice or in the patients?

A: My personal bias is that it's working at the level of the mitochondria [the energy-producing units of cells]. In the mice, we found the same effects in males and females, so that suggests that tamoxifen is having its beneficial effect in this ALS-like disorder at a location other than at the estrogen receptor, which is where it's thought to be working in breast cancer.

Another interesting observation is that tamoxifen inhibits an enzyme called neuronal nitric oxide synthase, which is thought to be involved in a death mechanism in nerve cells. This is new information, and we're going to be looking more at that.

Q: Some people are suggesting that viruses or other organisms, such as bacteria, could be involved in the ALS that's been associated with the Gulf War. What do you think about that?

A: You know, the issue of whether the incidence of ALS goes up after a traumatic upheaval goes back all the way to [19th-century French neurologist] Jean Martin Charcot. There were anecdotes that the incidence increased in the late 1870s, after the Franco-Prussian War.

Then, after World War I, particularly in Belgium, and after World War II on the island of Guam in the Pacific, there was the same question of increased ALS incidence.

Now, since the Gulf War, you can do a lot of this epidemiology with computer systems. The information available from the Department of Veterans Affairs and the Department of Defense says the rate of ALS was significantly increased in military personnel who served in the Gulf War in the Air Force and Army but not in the Navy or Marines.

But what does it mean? One study is looking at genetic predispositions in those who got ALS. One hypothesis is that there might be some SOD1 variations that make people more susceptible to ALS under certain conditions. [SOD1 is a gene that, when mutated, can cause ALS in humans and animals.]

Another hypothesis suggests that the ALS increase is related to toxic exposures.

Here at the Veterans Affairs Hospital in Madison, I've seen people who have had what is called Gulf War syndrome who are now developing neurological signs. This may be the tip of an iceberg. We may see more cases as we go further away from the exposure time. It may be that the exposure causes damage to neurons such that when the aging process interacts with that exposure, you get ALS.

Researchers at the University of Washington, Seattle, have found that patients who develop ALS at age 40 or 50 have sometimes had extraordinary exposures earlier in life. Some people have had significantly higher exposure to pesticides, for example, between ages 15 and 25. So, in this Gulf War group, a separation of 20 to 30 years could occur before we see a peak of ALS incidence.

Q: What other kinds of toxic exposures? Could it be a combination, say, of a microorganism and other toxic substances?

A: It's a possibility. There's an Australian disease that affects the motor neurons in cattle. If the cattle get a certain virus infection and also drink water with a certain chemical in it, they get the motor neuron disease. But either thing alone won't cause it. So, it could be that two things have to happen at once.

In the veterans, one toxic exposure might be something like lighting the lamps in the camps with diesel fuel or maybe being around the oil wells that were burning all the time. Then, on the virus issue, it could be there was something that they picked up over there, some seemingly benign cold or other virus, such as an enterovirus. Of course, genetic predisposition could be acting in this mix as well.

 

For information about participating in the tamoxifen trial, call (608) 262-7175 or (608) 263-9057, or e-mail alscrc@neurology.wisc.edu.

Margaret Wahl
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