July 13, 2005

Treatment Targets for ALS Identified in Cell Based Screening Tests

[QUICK SUMMARY: ALSA funded researchers have published information gathered by screening existing drugs in cell based tests that suggest possible avenues towards new ALS treatments.]

Existing drugs can help keep motor neurons alive in the lab, in cell culture tests that are helping scientists to discover new treatments for the nerve wasting disease ALS (amyotrophic lateral sclerosis), also called Lou Gehrig’s disease. The findings with these cell culture tests, reported in the March issue of the journal, Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders by investigators funded in part by The ALS Association, show that common mechanisms of action shared by certain drugs can explain why these compounds might be helping motor neurons in dishes, and point the way to the design of effective treatment of the disorder in people.

The investigators led by Eva Feldman, M.D., Ph.D., and Andrea Vincent, Ph.D., at the University of Michigan in Ann Arbor write in their report that the findings by no means imply that any of the drugs identified in the screening should be used immediately in the clinic. But eventually, the findings may lead to design of drug cocktails that protect motor neurons to promote quality of life and survival in ALS.

The drug screening effort was part of a joint project of The ALS Association (ALSA), the National Institute of Neurological Disorders and Stroke (NINDS), the Hereditary Disease Foundation (HDF), and the Huntington's Disease Society of America (HDSA). Investigators from 26 laboratories took part in the initial six-month, $1.3 million project, which tested 1,040 compounds using 29 different assays, or tests (see http://www.alsa.org/news/article.cfm?id=284).

Feldman’s team found that 78 of the drugs tested worked to lower the death rate of motor neurons cultured in the lab when these neurons were exposed to toxic amounts of the messenger molecule, glutamate. Glutamate normally conveys signals to neurons, but in excess, it can kill them. Mechanisms are normally in place for motor neurons that remove excess glutamate. Research has shown that the regulation of glutamate may be altered in ALS. Motor neurons die in the disease.

The Michigan researchers identified six ways that the drugs identified by the screening test are working within cells. Nearly all of the drugs that scored as positive “hits” in the cell testing work by one of these six mechanisms of action. For instance, certain drugs that lowered the death rate of motor neurons are known to stop the process of making proteins. Others are known to inhibit the inflammation provoking enzyme called cyclooxygenase (COX).

The screening effort has produced intriguing new information about the cell processes that may be tapped in order to alleviate the damage to motor neurons during ALS. The next step is to verify if the compounds of interest will work in more complex cell based tests, and then to move any continued successful compounds into animal testing to find useful combinations at optimal doses that show the most promise.

One candidate drug identified by the NINDS screening effort is slated to enter a new clinical trial.

Journal link:
http://taylorandfrancis.metapress.com/openurl.asp?genre=article&id=doi:10.1080/14660820510026171.