Abstract

The CRISPR/Cas9 system has revolutionized biomedical research and has created new opportunities for drug discovery. Evotec has fully integrated a CRISPR/Cas9 technology platform for target identification, validation, and genome engineering into its existing portfolio of state-of-the-art drug discovery services. Evotec offers comprehensive functional genetic screening for target identification, a powerful approach to identify novel disease-relevant targets in a genome-wide manner. We apply both pooled and arrayed screening using either lentivirus-based, lipofection-based or electroporation-based approaches depending on project requirements and biological context. In addition to experimental design and execution, Evotec provides sophisticated bioinformatic analysis of the screen results to aid with hit identification and annotation. Furthermore, we have developed approaches for genetic target validation, in advanced disease-relevant models such as primary cells and induced pluripotent stem cell (iPSC)-derived systems to follow up hits from genetic screens. Here we present two case studies: (1) a lentiviral pooled CRISPR dropout screen to identify novel druggable synthetic lethality partners for a genetic feature that causes a ”mutator” phenotype in many different tumour types followed by extensive target validation; and, (2) an arrayed RNP-based CRISPR screen in primary human T-cells with using a multi-colour FACS readout for novel target identification in immuno-oncology space at druggable genome level followed by target validation in multiple functional assays using purified different human primary T cell subsets. These two case studies exemplify integration of the CRISPR technology within Evotec´s comprehensive readout technologies for target identification followed by rapid transition from a target idea towards a validated target hypothesis feeding into target-based drug discovery.