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The state of CRISPR-Cas9 gene editing technology and applications for toxicology research (SOT 2021)
Citation:
Wehmas, L. The state of CRISPR-Cas9 gene editing technology and applications for toxicology research (SOT 2021). Society of Toxicology 2021 Annual Meeting (Symposium), Virtual, Florida, March 12 - 26, 2020. https://doi.org/10.23645/epacomptox.14466048
Impact/Purpose:
Presentation to the Virtual Society of Toxicology Annual Meeting March 2021. The gene editing technology Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas9 is revolutionizing basic biology, translational medicine, and increasingly, the field of toxicology. CRISPR-Cas9 silences or overexpress genes making it uniquely suited to facilitate adverse outcome pathway discovery and development. The roles of genes in toxicity can be functionally verified and linked to actionable regulatory outcomes pushing beyond associations to demonstrate mechanistic causality. This innovative technology has critical ramifications for hazard identification, chemical prioritization, risk assessment, and drug discovery. This introduction will present the state-of-the-science on CRISPR-Cas9 gene editing while discussing applications, advances, and the ramifications of this technology on the field of toxicology.
Description:
The gene editing technology Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas9 is revolutionizing basic biology, translational medicine, and increasingly, the field of toxicology. CRISPR-Cas9 silences or overexpress targets through non-homologous end joining or homology directed repair making it uniquely suited to facilitate adverse outcome pathway discovery and development. The roles of particular target molecules in pathways of toxicity can be functionally verified and linked to actionable regulatory outcomes with this technique pushing beyond associations to demonstrate mechanistic causality. This innovative technology has critical ramifications for hazard identification, chemical prioritization, risk assessment, and drug discovery. Gene editing can be conducted in a variety of cell types and animal models allowing for the translation of results across complex biological systems via validation of conserved toxicity pathways. The availability of many different guide RNA design strategies and genome wide knockout libraries allow for individual, multi, and genome-wide gene edits for positive and negative selection-based screening assays, while application of CRISPR-deactivated Cas9 can illuminate site-specific methylation/acetylation changes necessary to characterize chemical mediated epigenetic modes of toxicity. While most gene editing applications have focused on loss-of-function strategies to understand key toxicity events, homology directed repair can be used with CRISPR to insert or swap out gene targets for tailored gain-of-function mutations. This can not only assist in recapitulating a specific adverse outcome pathway or disease state, but also be coupled with single base pair editing to understand how common mutations in sensitive subpopulations impact chemical toxicant susceptibility. This introduction will present the state-of-the-science on CRISPR-Cas9 gene editing while discussing applications, advances, and the ramifications of this technology on the field of toxicology. This abstract does not represent US EPA policy.
URLs/Downloads:
DOI: The state of CRISPR-Cas9 gene editing technology and applications for toxicology research (SOT 2021)
20210222_SY21_SOT2021_WEHMAS_V8.PDF (PDF, NA pp, 1681.452 KB, about PDF)