Development of Novel Therapeutics
CII Project Staff
Georgios Asteris and Tim Clark
Collaborators
Alex Kazantsev (PI, Screening), Michele Maxwell, Steve Altman, Zane Hollingsworth, Greg Cuny (PI, Med Chem), Steve Hersch (PI, Animal Models), Marian DiFiglia (PI, Assays), David Housman and Anne Young (Program Director).
Description
This project is a collaboration between researchers at MIND, the Harvard Laboratory for Drug Discovery in Neurodegeneration (LDDN), MIT and other institutions to seek promising new experimental therapeutics for Huntington’s Disease.
HD affects over 25,000 individuals in the USA and there are more than 60,000 individuals who are likely gene positive. Although it affects only 5-10 persons/100,000, it is a significant health problem. Since effective therapy for HD would generate at most $500,000,000 annually the market has not been big enough to attract industry. Thus, effective therapies for HD must be sought in academic settings.
Scientific advances in the last five years have identified pathways apparently involved in the pathogenesis of Huntington’s disease (Fig. 1). The pathways include huntingtin cleavage, huntingtin clearance, degradation through the proteosome, aggregation, huntingtin transcription and huntingtin regulation of transcription. These mechanisms can be modeled in cell culture or cell free systems and we have discovered assays for these pathways that can be used for high throughput drug screening. Secondary assays of various cellular pathways have also been developed that complement the primary screens including studies in C. elegans and Drosophila. Finally, with transgenic animal models (truncated and full length) also available, all the pieces are in place to effectively mount a drug discovery for HD.
Figure 1
CII has worked closely with the laboratory of Alex Kazantsev and other PI's to develop the overall informatics approach, Core infrastructure, and quality assurance approach. We continue to work with our co-investigators to provide flexible and powerful informatics methods in support of the search for novel therapeutics in HD. Our objective is to enable high productivity of effort and fluid collaboration in the project across organizational boundaries.
The informatics program for this project consists of five main components:
• configure and put in place a stable and secure physical computing environment sufficiently capable for tasks (ii) through (v);
• provide software tools for data registration, capture and extraction, database management, data analysis, visualization, process control, quality control, in silico prediction, and statistical decision support analysis;
• provide databases and sharing/visualization mechanisms to permit a shared organizational memory and collaborative scientific practice to develop between physically separated groups, with high efficiency;
• provide advanced analytical expertise in cheminformatics and bioinformatics;
• develop specialized software as needed by the project team.
CII cheminformatics infrastructure for this project is principally based on the ID-BS cheminformatics toolkit and the ORACLE database server, running on MS Server2003 in a network-secure Partners computer facility. A conceptual model of our cheminformatics infrastructure as of May, 2005, is shown in figure 2.
Figure 2