By David N. Leff

Many diseases and syndromes are named for the practitioners who discovered them. Among ailments on which biotech researchers focus, these come to mind: Alzheimer¿s, Parkinson¿s, Huntington¿s, Duchenne, Gaucher¿s, Tourette¿s, Hodgkin¿s, Creutzfeldt-Jakob. Less well known ¿ at least by that name ¿ is Charcot¿s disease, or amyotrophic lateral sclerosis (ALS).

Jean-Martin Charcot (1825-1893), a leading 19th century pioneer of clinical neurology, described the chaotic zoo of neurological disorders he encountered and wrote of them that, ¿they defy the most penetrating anatomical investigations.¿

In recent decades, Charcot¿s ALS has become far more famous as Lou Gehrig¿s disease, honoring the celebrated Yankees batter of the 1920s and 30s, who died of the disease in 1941. Amyotrophic lateral sclerosis still defies the most penetrating investigations. (See BioWorld Today, Aug. 16, 1999, p. 1.)

One who labors to penetrate this mystery is neurosurgeon Robert Friedlander at the Harvard-affiliated Brigham and Women¿s Hospital in Boston. Last year, he reported a landmark finding, that apoptosis ¿ programmed cell death ¿ is implicated in the demise of brain neurons responsible for Huntington¿s disease (HD). (See BioWorld Today, May 20, 1999, p. 1.)

This year, in today¿s Science, dated April 14, 2000, Friedlander extends those findings from HD to ALS. In both neuronal disasters, he found that the principal perp is a family of proteins called caspases, key instigators of apoptosis. The Science paper, of which he is senior author, bears the title: ¿Functional role of caspase-1 and caspase-3 in the ALS transgenic mouse model.¿

The neuronal similarity between ALS and HD, Friedlander told BioWorld Today, ¿is very important, because there¿s a common thread running through all these chronic neurological diseases as to the first step in the death of those cells.

¿In HD we have a mutation,¿ he pointed out, ¿but we don¿t know how it causes the brain cell to become sick. In ALS,¿ he went on, ¿we know even a lot less, because in most of the patients we haven¿t identified their mutations, of which there are many. And we don¿t know what causes the disease or what starts its process.

¿The thing that HD has in common with ALS,¿ Friedlander added, ¿and probably also with Parkinson¿s and Alzheimer¿s ¿ is what¿s making their neurons sicken and die, at the end of the same process, as performed by these caspases.¿

Two Key Findings In Science Paper

¿From the basic scientific point of view, the one thing I¿m most excited about in this paper,¿ he said, ¿is that we¿re able to specifically detect in the neurons that are dying in ALS the activation of two of these apoptosis triggers ¿ caspase-1 and caspase-3. When we look at the human and murine spinal cords, we see only the cells that are being activated.

¿Our second finding,¿ he continued, ¿is the proof of principle in terms of administering a caspase inhibitor ¿ which is the same one we used last year in our HD report ¿ and to show that if we block these caspases, the ALS-model mice do better. Their disease starts later, its progress is slower and they die later. We¿re not only extending their survival at the end, when they¿re really very sick, but rather we¿re delaying the onset, making them stronger until the terminal stage of the disease.¿

This strategy of conserving vigor and postponing death is not without its critics.

¿One of the criticisms that people have,¿ Friedlander pointed out, ¿is that they think of caspase activity as the end-game. They say that when the cell is going to die is when these apoptosis guys get activated and kill the cells, so it¿s really not worthwhile inhibiting caspase, which would just be saving a cell that¿s already extremely sick.

¿This ALS article in Science and our previous HD study,¿ he went on, ¿demonstrate that such is not the case. In my opinion, what caspases are doing, when at first they become activated at a very low level, they¿re starting to make the cell sick. Therefore, blocking the caspases is going to delay that downhill process.

¿There are 14 caspases out there, ¿ he observed, ¿and I think that probably each one plays an important role within the pathway, which is not known. We know the most about caspases 1 and 3. In part, that¿s why we use this broad inhibitor that blocks all caspases, at the risk of having some side effects. At least in the mice, for the period we put in the drug, there were no obvious adverse reactions from broad caspase inhibition.¿

The transgenic ALS-modeling mice in the co-authors¿ experiments were created by neuroscientist Mark Gurney, now at Pharmacia Corp. in Kalamazoo, Mich. (he is also lead author of an editorial in today¿s Science commenting on Friedlander¿s adjacent paper). Gurney made his mice with a mutated human SOD (superoxide dismutase) gene from an ALS patient, which he inserted into mouse embryos. The progeny contracted ALS. Friedlander and his team then crossed those animals with mice that generated inhibitors of caspase-1 in their brains.

Neurons Unanimous On Caspase

¿In our latest ALS study,¿ he recounted, ¿we implanted micropumps into the brains of these mice and delivered the caspase inhibitor, starting at 60 days of life ¿ the presymptomatic or early stage of the disease ¿ then infused it for eight weeks. The treated animals, from a behavioral point of view, had later onset, progressed more slowly and died later. When we looked at their motor neurons, which were dying, the treatment significantly delayed their death.

¿We also looked at postmortem spinal cord tissue from humans with ALS and these, too, had elevated levels of caspase 1 activity.¿

With prime-of-life onset, ALS afflicts some 30,000 patients in the U.S. alone; 5,000 new cases occur annually. Death intervenes in three to five years following diagnosis. The only FDA-approved drug, riluzole (Rhone-Poulenc¿s Rilutek), has prolonged the lives of trial patients for three to four months. Creatinine has enhanced survival in mice.

¿ALS is a bad and difficult disease,¿ Friedlander observed. Like AIDS, one drug can¿t take care of it. You¿re going to need a combination of drugs, of which riluzole is probably one; creatinine might be another, and caspase inhibitors a third.¿