In vivo correction of a TP53 hotspot mutation by base editing induces tumor regression.

In vivo correction of a TP53 hotspot mutation by base editing induces tumor regression. | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Brief Communication In vivo correction of a TP53 hotspot mutation by base editing induces tumor regression. Shady Sayed, Therese Seidlitz, Kathleen Schmidt, Pascal Wang, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9643229/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Despite rapid advances in precision genome editing, most clinical applications have focused on monogenic disorders. In contrast, therapeutic mutation correction in cancer has remained largely unexplored. Here, we demonstrate in vivo correction of the recurrent TP53-R273H hotspot mutation using adenine base editing in a peritoneal cancer mouse model. Liposome-mediated delivery of optimized editor mRNA and mutation-specific guide RNA achieved efficient on-target editing with minimal off-target activity in vitro and in vivo. Mutation correction restored p53 pathway function and induced significant tumor regression without observable systemic toxicity. These findings provide in vivo proof-of-concept that precise correction of recurrent cancer driver mutations is feasible and therapeutically relevant, supporting precision mutation repair as a potential therapeutic modality in solid tumors. Biological sciences/Biotechnology/Gene therapy/Targeted gene repair Biological sciences/Cancer/Tumour-suppressor proteins Health sciences/Medical research/Preclinical research Full Text Additional Declarations There is NO Competing Interest. Supplementary Files Suppl.Table1.xlsx Protospacers and PCR primers used in the study Suppl.Table2.xlsx Sequences and genomic coordinates of predicted off-target sites Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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