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Correction of an oncogene mutation in glioma

Updated: 2020-02-28

Glioblastoma (GBM) is a kind of malignant brain tumor that seriously threatens human health and for which there is still no effective prevention and treatment method. Previous studies reported that 83% of primary glioblastoma carry an oncogene mutation in the promoter region of human telomerase reverse transcriptase (TERT) (Killela PJ, et al. PNAS 2013, PMID: 23530248), which reactivates the expression of TERT and drives the malignant progression of tumors. Therefore, precise correction of the oncogene mutation is a potential target for glioblastoma treatment.
On February 17, 2020, Researcher Li Xinjian of the Institute of Biophysics, Chinese Academy of Sciences, Professor Qian Xu of the School of Public Health, Nanjing Medical University, Professor Lv Zhimin from the Institute of Translational Medicine, Zhejiang University, and researchers from the University of Texas M.D. Anderson Cancer Center and Wenzhou Medical University published an article entitled Programmable base editing of mutated TERT promoter inhibits brain tumour growth (DOI: 10.1038/s41556-020-0471-6) in Nature Cell Biology. The study uses adeno-associated virus (AAV) as a vector to express the Campylobacter jejuni Cas9 fusion protein with adenine deaminase activity and the corresponding single guide RNA (sgRNA), so as to correct the oncogene mutation in the promoter region of TERT.
Located at the end of eukaryotic chromosomes, telomere consists of base repeats and binding proteins. The known function of telomere is to prevent degradation of chromosomal DNA and end fusion. The 5' end of normal cells disappears during linear DNA replication. As the cells continue to proliferate, the telomeres gradually shorten. When the telomeres have shrunk to a certain extent, the chromosomes become unstable, leading to cell senescence and cancer. Telomerase is a reverse transcriptase of telomere DNA. It uses RNA as a template and the 3' end of telomeres as primers to synthesize telomere repeats and maintain the length of chromosomal telomere DNA. Telomerase activity in normal human cells is very low. As the cells divide, telomeres continue to shorten until the cells stop dividing or die. To achieve unlimited proliferation, malignant tumor cells maintain the length of chromosomal telomeres through two mechanisms, namely mutations in the promoter region of TERT and alternative lengthening of telomeres (ALT), so as to avoid cell senescence. 
Modified from the prokaryotic acquired immune system, the CRISPR-Cas9 system can be used to edit the genomic DNA sequence of eukaryotic cells. Based on different hosts, Cas9 protein can be divided into Streptococcus pyogenes Cas9 (SpCas9), Staphylococcus aureus Cas9 (SaCas9), Campylobacter jejuni Cas9 (CjCas9) and other different types. In order to avoid base mismatches caused by repairing Cas9-mediated DNA double-strand breaks, researchers developed a base editing system that relies on the activities of adenine deaminase and SpCas9 nickase in 2017 (Gaudelli NM, et al. al. Nature 2017, PMID: 29160308). Based on this, this study replaced the original SpCas9 nickase with a CjCas9 nickase with a shorter gene coding sequence to express adenine deaminase-CjCas9 nickase fusion protein using adeno-associated viruses with limited encapsulation capacity. The fusion protein is named Campylobacter jejuniadenine base editor (CjABE). Adeno-associated viruses have advantages such as low immunogenicity, broad-spectrum host cells, and long-lasting expression time. In this study, adeno-associated viruses were used as the expression vector of the base editor CjABE to precisely correct the oncogene mutation in the promoter region of TERT. Local injection of adeno-associated viruses expressing CjABE can effectively inhibit the growth of transplanted tumors in mice and prolong the survival of tumor-bearing mice (Figure 1), suggesting that using CjABE to correct the oncogene mutation in the promoter region of TERT has potential clinical application value.
Figure 1: Researchers use adeno-associated virus (AAV) to express Campylobacter jejuniadenine base editor (CjABE). CjABE can precisely correct the oncogene mutation in the promoter region of TERT. Local injection of adeno-associated viruses expressing CjABE can effectively inhibit the growth of transplanted tumors in mice and prolong the survival of tumor-bearing mice.
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