Programmable base editing of mutated TERT promoter inhibits brain tumour growth.,Nature Cell Biology

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Programmable base editing of mutated TERT promoter inhibits brain tumour growth.
Nature Cell Biology ( IF 17.3 ) Pub Date : 2020-02-17 , DOI: 10.1038/s41556-020-0471-6
Xinjian Li _{1,

2} , Xu Qian _{3,

4} , Bin Wang _{1,

2} , Yan Xia _{5,

6} , Yanhua Zheng ₅ , Linyong Du ₇ , Daqian Xu ₅ , Dongming Xing _{8,

9} , Ronald A DePinho ₆ , Zhimin Lu ₁₀

Affiliation

CAS Key Laboratory of Infection and Immunity, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
University of Chinese Academy of Sciences, Beijing, China.
Department of Nutrition and Food Hygiene, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.
Institute for Brain Tumors, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.
Brain Tumor Center, Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, China.
School of Life Sciences, Tsinghua University, Beijing, China.
The Affiliated Hospital of Qingdao University and Qingdao Cancer Institute, Qingdao, China.
Department of Hepatobiliary and Pancreatic Surgery and Zhejiang Provincial Key Laboratory of Pancreatic Disease of The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China.

Clustered regularly interspaced short palindromic repeats (CRISPR), CRISPR interference and programmable base editing have transformed the manipulation of eukaryotic genomes for potential therapeutic applications1-4. 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 glioblastoma5-8. 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.

中文翻译：

突变的TERT启动子的可编程碱基编辑抑制了脑肿瘤的生长。

簇状规则间隔的短回文重复序列（CRISPR），CRISPR干扰和可编程碱基编辑已改变了真核基因组的操纵方式，可用于潜在的治疗应用1-4。在这里，我们利用CRISPR干扰和可编程碱基编辑来确定它们在编辑TERT基因启动子激活突变中的潜力，这种突变发生在许多不同类型的癌症中，尤其是胶质母细胞瘤5-8。使用单向导RNA（sgRNA）指导和催化受损的空肠弯曲杆菌CRISPR相关蛋白9融合腺嘌呤碱基编辑器（CjABE）将-124C> T TERT启动子突变校正为-124C。这种修饰阻止了E26转录因子家族成员与TERT启动子的结合，降低了TERT转录和TERT蛋白的表达，并诱导癌细胞衰老和增殖停滞。表达sgRNA指导的CjABE的腺相关病毒的局部注射抑制了具有TERT启动子突变的神经胶质瘤的生长。这些临床前的概念验证研究建立了基因编辑作为癌症治疗方法的可行性，并验证了激活的TERT启动子突变是癌症特异性的治疗靶标。

更新日期：2020-02-17

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