Workshop Reports

Workshop on Drug Discovery for Huntington's Disease
Royal Sonesta Hotel
Cambridge, Massachusetts
February 10-11, 2001
Prepared by Christine Sadlowski

Abstract
Thirty-three scientists pursuing a wide range of research interests convened for a two-day workshop sponsored by the Hereditary Disease Foundation (HDF). The purpose of the workshop was to focus current research efforts in Huntington's Disease (HD) on discovering and developing drug treatments for HD. Currently, no drugs are available that treat the cause of HD - mutations in the huntingtin gene that result in CAG repeats of varying lengths. Assays have been developed to test the effects of compounds at various stages of the purported HD pathological pathway. "Hits" (promising compounds) have begun to emerge from these assays. The main goals of the workshop were to identify criteria for selecting compounds for further testing and to determine the best procedure to follow once primary hits are identified. Speed and thoroughness are both important at this stage.

Several criteria for identifying lead compounds were discussed. However, it was generally agreed that it was too soon to choose criteria for all to follow. Participants agreed that all assays should continue in parallel, until some patterns begin to emerge. Mechanistic and phenominological assays should be developed for HD. Screens should begin with FDA2000 libraries of at least 1,000 compounds and move to larger libraries. Investigators must develop counterscreens for their assays, with potential deselection criteria including toxicity and suppression of expression from CMV or another promoter. An efficacy level of 10mM was proposed. Compounds effective in the nM range should be tested in mice. However, it was agreed that no hits should be discarded, because analogues might be more efficacious. Potency should be maximized before pharmacokinetics or in vivo efficacy studies.

Limiting factors were discussed, including costs, funding, research interests of invesigators and chemists, availability of libraries, screening speed, and intellectual property issues. Creation of a centralized facility for high-throughput screening was proposed, perhaps through the NINDS. Potential resources for assisting in moving compounds into the clinical trial stage include the NINDS epilepsy drug discovery program. Many participants expressed interest in a common database of hits, allowing individuals to make private arrangements for sharing and partnership. Hits might be sent out blind, with negative controls, and with several assays performed on the same set of compounds. The HDF might speed this process by facilitating it. It was also proposed that the HDF maintain an updated model of HD pathological pathways. The HDF might play a facilitating role in other ways, for example by funding of visits to the NIH for training. Several participants commented on the willingness of other participants to share information, and expressed the hope that intellectual property issues could be handled so that some of that openness might continue.

The following topics were covered:

1. Criteria for selecting compounds to move forward into animal and clinical trials
2. Other compound screening models
3. Current understanding of pathways of HD pathologies
4. Research updates from the participants' laboratories
5. The current state of compound libraries and plans for further library developments
6. The NINDS/NIH funding process, and how it applies to HD research