By Sean Henahan, Access Excellence

SAN FRANCISCO (3/30/96)- An enhanced understanding of the pathogenesis of ALS is translating into several promising drug treatment approaches for this disabling, always fatal disease, reported investigators at the 48th Annual Meeting of the American Academy of Neurology

ALS (amyotrophic lateral sclerosis), is a progressive neurodegenerative disease with symptoms including slurred speech, difficulty swallowing, spasticity, respiratory difficulty, and eventually immobility and death. ALS is marked by progressive deterioration of muscles (amyotrophy) occurring on one side of the body (lateral). A form of paralysis results as the motor neurons die and harden (sclerosis).

The disease affects an estimated 2.5 people per 100,000 population worldwide. The disease, also known as Motor Neuron Disease, Lou Gehrig's disease or maladie de Charcot, has a poor prognosis with death from respiratory failure usually occurring within five years of diagnosis.

Until recently there was little understanding of what caused the brain cell deterioration of ALS, nor was there any hope of treatment. Now researchers are focusing their efforts on three potential pathogenic pathways for the disease, according to Eva Feldman, M.D., Ph.D., Professor of Neurology, University of Michigan, Ann Arbor, MI.

The first pathway is neurotransmitter excitotoxicity. Research indicates that damage to brain cells from genetic and/or environmental causes leads to overproduction and/or impaired clearance of glutamate. Glutamate is the primary excitatory neurotransmitter in the brain, but excessive amounts lead to brain cell death.

This observation has led researchers to concentrate on developing agents that block this glutamate overload. One drug, riluzole, developed specifically to block glutamate in ALS, was recently approved for treatment of the disease. It is the currently the only approved drug for the treatment of ALS in the US. In clinical trials riluzole increased survival by 12%. While this may not seem like very much, this represented the first positive clinical results in the treatment of ALS, Dr. Feldman said.

Gabapentin is another drug currently in clinical trials that also blocks glutamate. The latest clinical data suggests that the drug was not effective, but there are reasons to believe a higher dose may provide some benefit. The drug is used for the treatment of epilepsy.

The second pathway of neuronal cell damage involves oxidative stress. This leads to overproduction of oxygen free radicals which in turn contributes to cellular destruction. This has led to the idea of using antioxidants, notably vitamin E, in ALS. There have been no major clinical trials with vitamin E and ALS, but many clinics, including teh Mayo Clinic, offer vitamin E to their ALS patients. There are animal studies suggesting it may be useful in delaying the onset of ALS disease symptoms. Again, finding the appropriate dose will be important, Dr. Feldman said.

The third cause of the neurodegeneration of ALS forming the basis for therapy is neurotrophic alteration. As the neurons begin to decline, they produce fewer and fewer essential growth factors, which hastens their death. This led to clinical trials where the goal is to replace absent or minimal growth factors with exogenous recombinant growth factors.

"Growth factors are a very exciting field and I believe they hold great promise not only for treatment of ALS but other chronic neurodegenerative diseases as well," Dr. Feldman said.

One such growth factor, IGF1 (insulin-like gropwth factor) is in the final stages of clinical trials and is expected to seek FDA approval shortly. IGF1 works in concert with growth hormone and has an important role in helping neurons divide, survive and differentiate. It also helps protect neurons from apoptosis (programmed cell death). The goal of treatment with the recombinant form of IGF1 is to stabilize neurons weakened by ALS.

In a recent large-scale clinical study, the patient group receiving the highest dose in the protocol showed statistically significant smaller declines in neurologic function than placebo after one month and throughout the nine month study. While placebo recipients showed declines associated with significant functional impairment, patients receiving the highest dose of IGF1 did not, Dr. Feldman reported.

"It is clear that IGF-1 changed the course of disease progression and functional severity. Patients also showed improved quality of life and the drug appeared to decrease the time to occurrence of death. In addition, no major safety concerns were identified during the study.

BDNF (brain derived neurotrophic factor) is another recombinant growth factor currently in clinical trials. In laboratory studies the growth factor appeared to increase motor neuron survival in animals. Results of early clinical trials announced at the conference showed some slowing in respiratory function decline, but no survival benefit after six months of treatment. There was some suggestion of benefit in the longer term. A larger trial with this drug is ongoing.

"The future direction of ALS treatment will probably involve some kind of combination therapy. We can learn from the cancer doctors. They don't use a single drug for a fatal disease, but multiple drug therapy. We now understand that multiple pathways contribute to ALS. Future trials might involve some combination of riluzole, vitamin E, and a growth factor like IGF1. These trials have been proposed to the NIH and hopefully will come to pass soon," she said.

Dr. Feldman spoke at the 48th Annual Meeting of the American Academy of Neurology, March 30, 1996, in San Francisco.

Related information on the Internet

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ALS Association Home Page

Medical Guide to ALS