Fast Tracks to Lead Compounds
January 6-7, 2001 o University of California Los Angeles Brain Research Institute
Gonda Goldschmeid Neuroscience Research Center, Los Angeles, California
Prepared by Marina Chicurel, Ph.D.
Abstract
The search for compounds to treat Huntington's disease (HD) can not proceed fast enough. Such was the sentiment inspired by those coping with HD, who generously shared their experiences at the January 2001 Hereditary Disease Foundation workshop. A 27-year-old woman, for example, described how her careers in architecture and modeling were truncated by the progressive symptoms of HD - uncontrollable movements and declining cognitive faculties. And a father bravely recounted how his son committed suicide only a few weeks earlier, to avoid the fate of his sister who is now living on a feeding tube as a result of HD.
The time seems ripe to begin developing treatments to lessen, or even eliminate, such suffering, but much work lies ahead. Much of the basic science of HD remains obscure. Little is understood, for example, of how expanded CAG repeats in the huntingtin gene lead to a vast array of cellular dysfunctions, and ultimately death, in selective regions of the brain. It is still unclear if a single molecular event triggers a cascade of downstream effects or if, alternatively, an initial event affects many cellular processes simultaneously. It is also uncertain whether mutated huntingtin mediates its primary effects by directly damaging the medium spiny cells in the striatum or by disrupting the function of the cortical neurons that project to the affected striatal cells. And although it is clear that a central aspect of HD pathology involves the formation of protein aggregates, the causal links between the size, composition, and density of these aggregates and the progression of disease are just beginning to surface.
Participants at the workshop recognized and discussed approaches to resolving these uncertainties. But they also noted that focusing efforts on a few of the molecular clues now available might yield therapeutic candidates, even at this early stage of research. Several strategies for screening compounds that specifically target long stretches of poly-glutamine repeats were presented. Assays to monitor the molecular structure, aggregation properties, expression, toxicity, proteolytic cleavage, and nuclear transport of polypeptides containing large poly-glutamine repeats emerged as promising options for finding and characterizing potentially therapeutic drugs.
From these screens, participants predicted that hundreds of candidate compounds are likely to emerge. The next challenge will be to whittle down the list for testing in animal models and, ultimately in clinical trials. By identifying rate-limiting steps, such as the availability of mice and the recruitment of neurologists, participants suggested ways to optimize the funneling process. They suggested outsourcing toxicological and pharmacokinetic studies, for example, to making testing in mice more manageable. And to increase the power of clinical trials, they proposed identifying improved genetic, pathological, and behavioral biomarkers of disease.
VIEW ENTIRE REPORT
|
