The document discusses how disruptive technologies such as RNA interference, stem cell technology, and human pluripotent stem cells could impact drug discovery by addressing some of its current challenges. It provides examples of how these technologies are being used in target identification and validation through RNAi screens and stem cell-derived disease models. While these technologies offer promising opportunities, challenges remain around delivery for RNAi therapies and generating fully differentiated and disease-relevant cell types from stem cells. The document advocates balancing vision for these technologies' potential with understanding the difficulties of integrating them into drug development.
5. A Strategy for Improving Translational Science Classical disease Target Leads Animal models of efficacy Candidates Broad PoC outcome studies Mechanistic disease Pathway Targets Leads Human 1 o cell models PD animal models Disease tissue Stratified PoC studies Candidates Mechanistically linked models with common PD biomarkers
6. siRNA screen of TNF-driven IL6 secretion in human RA synovial fibroblasts Normal knee joint Arthritic knee joint Synovial fibroblast culture Response to TNF established and intervention with siRNA validated Screen druggable genome siRNA library Validate hits in independent synovial fibroblast culture Assess robustness of screen and identify hits Example 1: Target selection in human disease cell siRNA screen
7. Example 2a: Target validation in human primary cells siRNA studies in stimulated primary CD4+ cells Target A (TCR response) Profound inhibition of key cytokines in Rheumatoid Arthritis (TNF ) and Asthma (IL13) 0 1000 2000 3000 4000 5000 6000 7000 TNFa IL13 pg/ml Control T Target A
8. Example 2b: Target validation in disease tissue Allergen-specific T cell responses in asthma Effect of drug on secretion of Cytokines and other Mediators Supernatant allergic asthmatic biopsy material Allergen ± Drug p=0.02 Unchallenged allergen challenged allergen challenged +drug Effect of tool compound to Target A on IL-5 release
9. Example 3: RNA PD markers from cell to clinic PDE4i Placebo Validation of gene signature in human primary cells dosed with cAMP activating drugs Gene expression signature in nasal epithelial from rodents dosed with drug POC study in allergen challenge chamber with nasal drug dosing Engagement of mechanism confirmed by gene expression signature in nasal scrapes
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15. Differentiated Cell Types Being developed, DA neurons most advanced More relevant models Specific neurons Being developed Diabetes/metabolic research Pancreatic cells Ready for initial deployment Drug metabolism Hepatocytes Ready for initial deployment Cardiotoxicity testing including long QT, target validation, efficacy testing Cardiomyocytes Ready for initial deployment Biological models for target validation, efficacy testing Neurons Status Major uses in drug development Cell type
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