Abstract

Target Validation Platforms for Inflammatory Disorders and Chronic Kidney Disease – the Power of Stem Cells and Precise Genome Editing

Ryan Hicks, Associate Director, AstraZeneca

Development of physiologically relevant cellular models, with strong translatability to human pathophysiology, is critical for identification and validation of novel therapeutic targets. Cell types derived from induced pluripotent stem cells (iPSCs) provide an important resource for modelling native biology in human cells and tissues for drug discovery. Understanding the phenotypic and functional relevance of these iPSC derived cells and tissues and how well they represent human biology is vital and as such we have developed tool iPSC-lines and techniques to optimize and monitor differentiation. Applying CRISPR/Cas9, Next Generation Sequencing (NGS), functional testing and advanced imaging techniques to iPSC model validation, we have established a platform that enables an accurate assessment of their benefits, maturity, gaps and challenges. Data presented are from two of the model systems we have developed. The first will describe the validation of a kidney model, using SIX2 and NPHS1 markers non-invasively in real-time, to trace early nephron commitment and podocyte-maturation in the same cell. The second case will describe how we use transcriptomic analysis by NGS, in addition to functional assays, to determine how well an iPSC derived immune-cell model compares to the equivalent primary cell model.