Combining hiPSCs and Human Genetics: Major Applications in Drug Development  Jin Zhang, Hu Li, Alan Trounson, Joseph C. Wu, Paul Nioi  Cell Stem Cell  Volume 21, Issue 2, Pages 161-165 (August 2017) DOI: 10.1016/j.stem.2017.07.012 Copyright © 2017 Elsevier Inc. Terms and Conditions

Figure 1 Combining Human Genetics with Stem Cell Models for Drug Development (A) Major applications and (B) unmet needs and challenges. ADR, adverse drug reactions; PD, pharmacodynamics; PK, pharmacokinetics. Cell Stem Cell 2017 21, 161-165DOI: (10.1016/j.stem.2017.07.012) Copyright © 2017 Elsevier Inc. Terms and Conditions

Figure 2 Strategies of Combining hiPSCs and Human Genetics for Drug Development (A) hiPSC-based forward and reverse pharmacology, and (B) illustration of a pooled genetic screen of variants using an hiPSC platform. First, variants associated with a complex disease are prioritized based on their association p value, effect size, functional annotation (i.e., disrupting a gene versus influencing a regulatory region), and tissue expression pattern. For non-coding variants, it is crucial to map them to susceptible genes with information about epigenetic modification, chromatin interaction, and expression quantitative trait loci (eQTL). Second, a pooled gRNA library designed to perturb/modulate the nominated genes’ expression is transduced to hiPSCs expressing a CAS9 or dCAS9-KRAB that can be induced after differentiation. If the phenotypic readout cannot be easily reduced to a single measurement such as survival or marker gene expression, single-cell RNA-seq, such as the recently developed “Perturb-seq” technology, can be used to inform cell states that reflect disease phenotypes. Finally, selected candidates need to be validated by a suite of surrogate assays representing disease phenotypes among isogenic iPSC lines or animal models. ES, effect size. Cell Stem Cell 2017 21, 161-165DOI: (10.1016/j.stem.2017.07.012) Copyright © 2017 Elsevier Inc. Terms and Conditions