By David N. Leff

Anhedonia is neither the name of a fictional kingdom nor of a Cunard ocean-liner. Rather, it¿s a psychopathic state of mind defined as the absence of pleasure from normally pleasurable situations.

Thus, anhedonia often is the first noticeable symptom to emerge in people afflicted with Huntington¿s disease (HD). It appears when the individual is in his or her mid-30s to 50s, well after the childbearing years. That means offspring run a 50-50 risk of themselves inheriting HD, with its devastating mix of dementia and uncontrollable movements.

HD is inexorably progressive, inevitably fatal and totally untreatable. But that¿s not for lack of trying by research neurologists in many countries. Cloning of HD¿s mutated gene, huntingtin, in the early 1990s, and of that gene¿s protein product, huntingtin, marked giant steps forward, but they came up against one blank wall: So far, nothing is known of how that protein functions.

Meanwhile, other lines of inquiry are making headway.

Neurosurgeon Robert Friedlander, at the Harvard-affiliated Brigham and Women¿s Hospital in Boston, pursued one hypothesis. Its fruits appear in today¿s issue of Nature, dated May 20, 1999. His paper is titled: ¿Inhibition of caspase-1 slows disease progression in a mouse model of Huntington¿s disease.¿

¿There¿s a significant amount of evidence,¿ Friedlander told BioWorld Today, ¿that apoptosis ¿ programmed cell death ¿ plays a role in the brains of HD patients. The hypothesis is that since we¿ve found in other brain diseases ¿ for example, stroke, amyotrophic lateral sclerosis [ALS] and head trauma ¿ that the apoptosis-promoting protein, caspase-1, plays an important role, we wanted to evaluate that role in HD.¿

Just as Friedlander and his co-authors were moving into this work, he recalled, ¿our hypothesis got nice corroboration from newly published Canadian research showing that caspase-1 itself can cleave and process the huntingtin protein.¿ Now, in their Nature paper, his group ¿reported for the first time detection of caspase-1 activation in the brains of transgenic mouse models of HD and in human HD brain cells. It shows,¿ Friedlander observed, ¿that there¿s a relevance of mice to humans.¿

According to the co-authors¿ findings, caspase-1 causes apoptosis, and apoptosis causes the death of neurons that are lost in HD brains. To reach this conclusion, they tested the effects of inhibiting caspase in two series of mice.

HD transgenic mice start out in life healthy, as do humans with the latent disease. But by 5 to 7 weeks of age, the animals begin to lose brain and body weight. At 9 weeks they start to develop irregular gait, shuddering movements, tremors and epileptic seizures.

¿The brains of these mice,¿ Friedlander recounted, ¿show that as they are getting sicker, they are losing the number of neurotransmitter receptors in their neurons ¿ for adenosine, for dopamine, for different neuroreceptors. This is an important feature, because that¿s probably what makes these mice HD-symptomatic.¿

Clobbering Apoptosis Saves Neurons¿ Lives

In that standard HD model, the co-authors raised litters of mice that expressed caspase-1 genes they had crippled by a point mutation, and thus were unable to trigger cell death. ¿And by expressing that genetic caspase-1 inhibitor,¿ Friedlander recalled, ¿we delayed the decrease in their receptor numbers.

¿Putting all that together,¿ he went on, ¿the next step was testing a broader, multi-caspase inhibitor, a synthetic drug agent code-named zVAD/FMK, to see if we could mimic the effects that we saw by genetically inhibiting caspase-1 alone.¿

In this pharmacological experiment, his team continuously pumped the inhibiting drug into the HD-mouse models¿ brains for four weeks. ¿By using this broad caspase inhibitor,¿ Friedlander continued, ¿we delayed the mortality of the mice ¿ again suggesting that this family of drugs would be useful for the treatment of human HD ¿ a disease for which at present there¿s no effective therapy.

¿The zVAD/FMK is a tripeptide,¿ Friedlander explained. ¿It was designed a few years ago by Enzyme Systems Products Inc. [in Livermore, Calif.] to fit into the active site of the caspases, and inhibit them. However, the problem with this particular agent is that it¿s never going to pass FDA approval, because of other toxicities. But many pharmaceutical companies are working toward making tolerable drugs, again by identifying that this family of caspase inhibitors is effective in this disease.¿

Then his team proceeded to crossbreed the standard HD mice with that transgenic strain they had raised, which encodes the mutant caspase-1 inhibitor in their brains. ¿As a result of this cross,¿ Friedlander observed, ¿we got littermates that only expressed the mutant huntingtin protein gene and got HD. Or mice that express both the HD gene plus the inhibitor.

¿Our overall mouse results tell us,¿ he summed up, ¿that if we inhibit caspase-1, the mice do a lot better; they survive longer, [and] their disease starts later and progresses more slowly. The useful part of their life is prolonged. That¿s part of the bottom line.¿

HD Drugs In Sight ¿ But Far Out

¿However,¿ he allowed, ¿translating these murine HD results to the human condition would be tough. You¿d have to use it with genetic engineering ¿ somehow gene transfer ¿ and I think that would be very difficult in adults right now. But it¿s not out of the question in the future.¿

In the bodies of all mammals, Friedlander noted, ¿caspase resides inactive until needed for apoptosis, or becomes aberrantly activated in some diseases, as it did in HD. What activates it,¿ he pointed out, ¿is something caused by the mutant huntingtin, but what activates it is not known.

¿One of the things that¿s most exciting to me,¿ he observed, ¿is that since we found this apoptotic effect activated in other brain diseases ¿ stroke, brain trauma and ALS, among others ¿ it seems that there are many different stimuli that can cause a neuron to die or become sick.

¿But then there¿s a shared common caspase pathway which mediates that effect. So something that¿s effective in the treatment of HD has a very good chance of being effective in some of these other diseases where caspases play a role. So whatever lessons we learn from treating HD, there¿s a good chance it would be applicable to a broad variety of neurological diseases.¿

While pursuing this wider inquiry, Friedlander concluded, ¿We¿re waiting for a biotech company to make a drug that we can test in humans.¿