The application of large-scale genetic association studies to impact drug discovery
GSK initiated the HiTDIP program (High Throughput human-Disease specific target Program) to identify targets genetically associated with human disease. The premise is that identification of disease associated drug targets will reduce attrition in the drug discovery pipeline. Over the next several years, the value of HiTDIP in enhancing drug discovery can then be evaluated against historical methods of target selection.
In conjunction with physician collaborators, subjects have been recruited for large, well phenotyped case/control collections for common human diseases in respiratory, inflammatory, musculoskeletal, cardiovascular, metabolic, neurological and psychiatric disease areas. These collections (~1000 cases/1000 controls) have been genotyped for ~6800 SNPs representing ~2000 target genes (such as 7TMs, kinases and ion channels) and tested for association to disease status. Results have been delivered for six collections. Well-known associations have been identified such as the HLA region in rheumatoid arthritis and APOE in Alzheimer’s disease. In addition, novel targets have been identified for given therapeutic areas. In some cases the targets have existing compounds for assay development, chemical leads for proof of concept studies, or are in Phase I clinical trials for an alternate indication. These targets represent opportunities to accelerate the typical drug development process.
Progress will be presented, focusing on results obtained for obesity. In addition, the opportunities to extend this candidate gene study to query the genome using high density SNP marker panels will be discussed. Well-phenotyped collections, coupled with an infrastructure for high-throughput genotyping and analysis will enable more efficient target selection matched to the relevant human therapeutic indication. Furthermore, information on genes associated with disease will also be relevant to the assessment of the appropriate clinical population for drug development.