Programmable base editing of mutated TERT promoter inhibits brain tumour growth
Xinjian Li, Xu Qian, Bin Wang, Yan Xia, Yanhua Zheng, Linyong Du, Daqian Xu, Dongming Xing, Ronald A. DePinho & Zhimin Lu
Abstract
Clustered regularly interspaced short palindromic repeats (CRISPR), CRISPR interference and programmable base editing have transformed the manipulation of eukaryotic genomes for potential therapeutic applications1,2,3,4. Here, we exploited CRISPR interference and programmable base editing to determine their potential in editing a TERT gene promoter-activating mutation, which occurs in many diverse cancer types, particularly glioblastoma5,6,7,8. Correction of the ？124C>T TERT promoter mutation to ？124C was achieved using a single guide RNA (sgRNA)-guided and catalytically impaired Campylobacter jejuni CRISPR-associated protein 9-fused adenine base editor (CjABE). This modification blocked the binding of members of the E26 transcription factor family to the TERT promoter, reduced TERT transcription and TERT protein expression, and induced cancer-cell senescence and proliferative arrest. Local injection of adeno-associated viruses expressing sgRNA-guided CjABE inhibited the growth of gliomas harbouring TERT-promoter mutations. These preclinical proof-of-concept studies establish the feasibility of gene editing as a therapeutic approach for cancer and validate activated TERT-promoter mutations as a cancer-specific therapeutic target.
附件下载：
Programmable base editing of mutated TERT promoter inhibits brain tumour growth, Nat Cell Biol, 17 Feb 2020
Nature Cell Biology, 17 February, 2020，DOI：https://doi.org/10.1038/s41556-020-0471-6
Programmable base editing of mutated TERT promoter inhibits brain tumour growth
Xinjian Li, Xu Qian, Bin Wang, Yan Xia, Yanhua Zheng, Linyong Du, Daqian Xu, Dongming Xing, Ronald A. DePinho & Zhimin Lu
Abstract
Clustered regularly interspaced short palindromic repeats (CRISPR), CRISPR interference and programmable base editing have transformed the manipulation of eukaryotic genomes for potential therapeutic applications1,2,3,4. Here, we exploited CRISPR interference and programmable base editing to determine their potential in editing a TERT gene promoter-activating mutation, which occurs in many diverse cancer types, particularly glioblastoma5,6,7,8. Correction of the ？124C>T TERT promoter mutation to ？124C was achieved using a single guide RNA (sgRNA)-guided and catalytically impaired Campylobacter jejuni CRISPR-associated protein 9-fused adenine base editor (CjABE). This modification blocked the binding of members of the E26 transcription factor family to the TERT promoter, reduced TERT transcription and TERT protein expression, and induced cancer-cell senescence and proliferative arrest. Local injection of adeno-associated viruses expressing sgRNA-guided CjABE inhibited the growth of gliomas harbouring TERT-promoter mutations. These preclinical proof-of-concept studies establish the feasibility of gene editing as a therapeutic approach for cancer and validate activated TERT-promoter mutations as a cancer-specific therapeutic target.
文章链接：https://www.nature.com/articles/s41556-020-0471-6
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