碱基编辑

碱基编辑

碱基编辑技术通过“效应器”和“定位器”相结合，在靶向位点完成碱基转换，从而实现基因组编辑和改写。


图片关键词

碱基编辑与CRISPR介导的基因编辑相比的优势


目前已知超过75,000种基因突变会导致人类疾病，如地中海贫血、杜兴氏肌肉营养不良症等。绝大部分由基因突变所导致的遗传性疾病无药可医，而对于其中小部分病种，患者往往需要终生服药，并承受药物带来的副作用和心理压力。遗传性疾病中约一半是由单碱基突变导致，这类突变难以利用传统的基因编辑工具进行修复。而碱基编辑技术不仅能够在庞大的基因组中精准、永久地改变单个碱基对，还可以根据不同疾病的突变位点对其进行自由组合，为点突变引起的遗传性疾病的治愈以及癌症的免疫治疗提供了新的可能。


前几代基因编辑技术分别为ZFNs、TALENs和CRISPR/Cas9，其共同特点是通过完全切断DNA双链造成double strand break来进行重新整合修复基因，被称为“分子剪刀”或“分子魔剪”。这些技术均可能造成由DNA双链断裂而带来的大片段染色体缺失、染色体易位等安全问题。


如果说CRISPR/Cas9是一把剪刀，需要通过把DNA双链剪断才能进行编辑，那Base Editing碱基编辑技术就是一支笔，在完全保证DNA双链完整性的同时就可以对错误的碱基进行校正，因此不会促发p53通路激活和染色体异常等安全风险，实现了“化刀为笔”的精确修复，同时也确保了高效编辑和安全性。碱基编辑技术从根本上解决了前几代基因编辑技术引发DNA双链断裂而造成的大片段染色体缺失、染色体易位等源头问题，在人类疾病治疗的应用上，其安全性和成药性都有本质的提升。有一个更加具象的比喻，碱基编辑把基因编辑从风险性高的开胸手术变成了简易安全的微创手术，精准修复，降低风险。


图片关键词

知识产权

拥有碱基编辑体系底层平台性自主知识产权的碱基编辑器


正序生物科学创始人团队至今已开发出5大系列的碱基编辑系统，其中增强型碱基编辑器eBE（enhanced Base Editor）于2020年12月获得中国专利授权，变形式碱基编辑器tBE（transformer Base Editor）于2022年7月获得美国专利授权，其他多项碱基编辑技术也提交了PCT国际专利申请，覆盖全球15个国家和地区。

新型高精准变形式碱基编辑系统


其中，由正序生物科学创始人团队开发的新型高精准碱基编辑器tBE（transformer Base Editor），将普通碱基编辑器存在的全基因组以及全转录组的脱靶突变完全消除，同时还保持了在靶向位点处的高编辑效率(tBE, Nature Cell Biology, 2021)，成为目前已开发的胞嘧啶碱基编辑器中消除脱靶突变和实现靶向编辑综合能力最好的碱基编辑器。通过巧妙的“锁”的设计，tBE只在靶向位点时编辑功能才能“解锁”，而在非靶向位点时编辑功能失效，从而实现了高效无脱靶的精准编辑效果。同时，tBE灵活的“变形金刚式”多元件组合方法更完美地契合包括AAV、mRNA/LNP等多种体内递送方式的需求，大大提高了其体内碱基编辑的效率。此外，tBE在可成药靶点处还可以同时实现多个靶点的精准高效编辑。相对于现有的碱基编辑系统，这些优势都极大地扩展了tBE在临床治疗的应用范围。


图片关键词

▲ 正序生物新型高精准变形式碱基编辑器tBE（transformer Base Editor）

（Han et al., Nature Protocols, 2023）


编辑疗法

碱基编辑疗法

正序生物利用以tBE为代表的碱基编辑系统开创的精准碱基编辑疗法，不仅可应用于体外（ex vivo），还能应用于体内（in vivo），能直接对突变基因进行修复，可应用于几乎所有遗传病。而利用传统基因替代方法进行治疗时，突变基因仍然存在，无法应用于所有遗传性疾病治疗，终身治疗效果有待验证。相比较Cas nuclease和Regular BE的基因编辑疗法，利用tBE开创的新型碱基编辑疗法具有最为安全的防脱靶保证、更高的靶向编辑效率、更好的治疗效果以及更低的细胞毒性。


图片关键词

▲ 正序生物体外基因编辑疗法流程

研究成果

  研究论文
  综述、评论、访谈

1. Guangye Li#, Guo Chen#, Guo-Hua Yuan#, Jia Wei#, Qingyang Ni, Jing Wu, Bei Yang, Li Yang*, Jia Chen*. Specific and efficient RNA A-to-I editing through cleavage of an ADAR inhibitor. Nat Biotechnol, 2025, doi: 10.1038/s41587-025-02591-2.

 

2. Yuhang Fan#, Wenchao Xu#, Bao-Qing Gao#, Huichao Qin, Xiaoyi Wu, Jia Wei, Qingyang Ni, Lina Zhou, Jiangchao Xiang, Jing Wu, Bei Yang, Li Yang, Jia Chen*. Leveraging base excision repair for efficient adenine base editing of mitochondrial DNA. Nat Biotechnol, 2025, doi: 10.1038/s41587-025-02608-w.

 

3. Qimingxing Chen#, Yan Chang#, Xiaoyan He, Yan Ding, Runyuan Wang, Ran Luo, Jialu Yuan, Jiabei Chen, Guisheng Zhong, Huiying Yang, Jia Chen*, Jianfeng Li*. Targeted delivery of mRNA with polymer–lipid nanoparticles for in vivo base editing. ACS NANO, Feb 2025, 19(8): 7835–7850.

 

4. Wenyan Han#, Hou-Yuan Qiu#, Shangwu Sun#, Zhi-Can Fu#, Guo-Quan Wang#, Xiaowen Qian#, Lijie Wang, Xiaowen Zhai, Jia Wei, Yichuan Wang, Yi-Lin Guo, Guo-Hua Cao, Rui-Jin Ji, Yi-Zhou Zhang, Hongxia Ma, Hongsheng Wang, Mingli Zhao, Jing Wu, Lili Bi, Qiu-Bing Chen, Zifeng Li, Ling Yu, Xiaodun Mou, Hao Yin, Li Yang*, Jia Chen*, Bei Yang*, Ying Zhang*. Therapeutic base editing of the HBG promoter reactivates γ-globin expression with no detectable off-target mutations in beta-thalassemia HSCs. Cell Stem Cell, 2023, 30(12): 1624-1639.e8.

 

5. Wenyan Han#, Baoqing Gao#, Junjie Zhu#, Zongxing He#, Jianfeng Li*, Li Yang*, Jia Chen*. Design and application of the transformer base editor in mammalian cells and mice. Nat Protoc, 2023, 18(11): 3194-3228.

 

6. Wenwen Zhao#, Jifang Li#, Xiao Wang#, Wei Xu#, Baoqing Gao#, Jiangchao Xiang, Yaofeng Hou, Wei Liu, Jing Wu, Qilian Qi, Jia Wei, Xiaoyu Yang, Lu Lu*, Li Yang*, Jia Chen*, Bei Yang*. Prime editor-mediated functional reshaping of ACE2 prevents the entry of multiple human coronaviruses, including SARS-CoV-2variants. MedComm, 2023, 4: e356.

 

7. Xiaosa Li#*, Lina Zhou#, Bao-Qing Gao#, Guangye Li, Xiao Wang, Ying Wang, Jia Wei, Wenyan Han, Zixian Wang, Jifang Li, Runze Gao, Junjie Zhu, Wenchao Xu, Jing Wu, Bei Yang, Xiaodong Sun*, Li Yang*, Jia Chen*. Highly efficient prime editing by introducing same-sense mutations in pegRNA or stabilizing its structure. Nat Commun, 2022, 13: 1669


8. Runze Gao#, Zhi-Can Fu#, Xiangyang Li#, Ying Wang#, Jia Wei, Guangye Li, Lijie Wang, Jing Wu, Xingxu Huang*, Li Yang*, and Jia Chen*. Genomic and transcriptomic analyses of prime editing guide RNA-independent off-target effects by prime editors. CRISPR J, 2022, 5(2): 276-293.


9. Jinlin Wang#, Zhou He#, Guoquan Wang#, Ruiwen Zhang#, Junyi Duan, Pan Gao, Xinlin Lei, Houyuan Qiu, Chuanping Zhang, Ying Zhang & Hao Yin*. Efficient targeted insertion of large DNA fragments without DNA donors. Nat Methods, 2022, 19(3): 331-340.

 

10. Xiang Gao#, Xu-Kai Ma#, Xiang Li, Guo-Wei Li, Chu-Xiao Liu, Jun Zhang, Ying Wang, Jia Wei, Jia Chen, Ling-Ling Chen & Li Yang*. Knockout of circRNAs by base editing back-splice sites of circularized exons. Genome Biol, 2022, 23: 16.

 

11. Lijie Wang#, Wei Xue#, Hongxia Zhang#, Runze Gao#, Houyuan Qiu#, Jia Wei, Lina Zhou, Yun-Ni Lei, Xiaocheng Wu, Xiao Li, Chengfang Liu, Jing Wu, Qiubing Chen, Hanhui Ma, Xingxu Huang, Cheguo Cai, Ying Zhang, Bei Yang*, Hao Yin*, Li Yang* & Jia Chen*. Eliminating base-editor-induced genome-wide and transcriptome-wide off-target mutations. Nat Cell Biol, 2021, 23(5): 552-563.

 

12. Xiao Wang#, Chengfeng Ding#, Wenxia Yu#, Ying Wang#, Siting He#, Bei Yang#, Yi-Chun Xiong, Jia Wei, Jifang Li, Jiayi Liang, Zongyang Lu, Wei Zhu, Jing Wu, Zhi Zhou, Xingxu Huang, Zhen Liu*, Li Yang* & Jia Chen*. Cas12a Base editors induce efficient and specific editing with low DNA damage response. Cell Rep, 2020, 31(9): 107723.

 

13. Chun-Qing Song#, Tingting Jiang#, Michelle Richter, Luke H Rhym, Luke W Koblan, Maria Paz Zafra, Emma M Schatoff, Jordan L Doman, Yueying Cao, Lukas E Dow, Lihua Julie Zhu, Daniel G Anderson, David R Liu*, Hao Yin*, Wen Xue*. Adenine base editing in an adult mouse model of tyrosinaemia. Nat Biomed Eng, 2020, 4: 125-130.

 

14. Ying Wang#, Runze Gao#, Jing Wu#, Yi-Chun Xiong, Jia Wei, Sipin Zhang, Bei Yang, Jia Chen* and Li Yang*. Comparison of cytosine base editors and development of the BEable-GPS database for targeting pathogenic SNVs. Genome Biol, 2019, 20(1): 218.

 

15. Xiao Wang#, Jianan Li#, Ying Wang#, Bei Yang#, Jia Wei#, Jing Wu, Ruixuan Wang, Xingxu Huang*, Jia Chen* and Li Yang*. Efficient base editing in methylated regions with a human APOBEC3A-Cas9 fusion. Nat Biotechnol, 2018, 36(10): 946-949.

 

16. Xiaosa Li#, Ying Wang#, Yajing Liu#, Bei Yang#, Xiao Wang, Jia Wei, Zongyang Lu, Yuxi Zhang, Jing Wu, Xingxu Huang*, Li Yang* and Jia Chen*. Base editing with a Cpf1-cytidine deaminase fusion. Nat Biotechnol, 2018, 36(4): 324-327.

 

17. Jian-Feng Xiang#, Qin Yang#, Chu-Xiao Liu#, Man Wu, Ling-Ling Chen*, Li Yang*. N(6)-Methyladenosines Modulate A-to-I RNA Editing. Mol Cell, 2018, 69(1): 126-135 e126.

 

18. Liqun Lei#, Hongquan Chen#, Wei Xue#, Bei Yang#, Bian Hu#, Jia Wei, Lijie Wang, Yiqiang Cui, Wei Li, Jianying Wang, Lei Yan, Wanjing Shang, Jimin Gao, Jiahao Sha, Min Zhuang, Xingxu Huang, Bin Shen*, Li Yang* and Jia Chen*. APOBEC3 induces mutations during repair of CRISPR-Cas9-generated DNA breaks. Nat Struct Mol Biol, 2018, 25(1): 45-52.

 

19. Hao Yin#, Chun-Qing Song#, Sneha Suresh, Suet-Yan Kwan, Qiongqiong Wu, Stephen Walsh, Junmei Ding, Roman L Bogorad, Lihua Julie Zhu, Scot A Wolfe, Victor Koteliansky, Wen Xue*, Robert Langer* & Daniel G Anderson*. Partial DNA-guided Cas9 enables genome editing with reduced off-target activity. Nat Chem Biol, 2018, 14(3): 311-316.

 

20. Lijie Wang#, Wei Xue#, Lei Yan#, Xiaosa Li, Jia Wei, Miaomiao Chen, Jing Wu, Bei Yang*, Li Yang* and Jia Chen*. Enhanced base editing by co-expression of free uracil DNA glycosylase inhibitor. Cell Res, 2017, 27(10): 1289-1292.

 

21. Hao Yin, Chun-Qing Song, Sneha Suresh, Qiongqiong Wu, Stephen Walsh, Luke Hyunsik Rhym, Esther Mintzer, Mehmet Fatih Bolukbasi, Lihua Julie Zhu, Kevin Kauffman, Haiwei Mou, Alicia Oberholzer, Junmei Ding, Suet-Yan Kwan, Roman L Bogorad, Timofei Zatsepin, Victor Koteliansky, Scot A Wolfe, Wen Xue, Robert Langer & Daniel G Anderson*. Structure-guided chemical modification of guide RNA enables potent non-viral in vivo genome editing. Nat Biotechnol, 2017, 35(12): 1179-1187.

 

22. Hao Yin, Chun-Qing Song, Joseph R Dorkin, Lihua J Zhu, Yingxiang Li, Qiongqiong Wu, Angela Park, Junghoon Yang, Sneha Suresh, Aizhan Bizhanova, Ankit Gupta, Mehmet F Bolukbasi, Stephen Walsh, Roman L Bogorad, Guangping Gao, Zhiping Weng, Yizhou Dong, Victor Koteliansky, Scot A Wolfe, Robert Langer, Wen Xue* & Daniel G Anderson*. Therapeutic genome editing by combined viral and non-viral delivery of CRISPR system components in vivo. Nat Biotechnol, 2016, 34(3): 328-33.

 

23. Xiao-Ou Zhang#, Hai-Bin Wang#, Yang Zhang, Xuhua Lu, Ling-Ling Chen*, and Li Yang*. Complementary sequence-mediated exon circularization. Cell, 2014, 159(1): 134-147.

 

24. Hao Yin#, Wen Xue#, Sidi Chen, Roman L Bogorad, Eric Benedetti, Markus Grompe, Victor Koteliansky, Phillip A Sharp, Tyler Jacks & Daniel G Anderson*. Genome editing with Cas9 in adult mice corrects a disease mutation and phenotype. Nat Biotechnol, 2014, 32(6): 551-553.

 

25. Wen Xue#, Sidi Chen#, Hao Yin#, Tuomas Tammela, Thales Papagiannakopoulos, Nikhil S. Joshi, Wenxin Cai, Gillian Yang, Roderick Bronson, Denise G. Crowley, Feng Zhang, Daniel G. Anderson, Phillip A. Sharp & Tyler Jacks*. CRISPR-mediated direct mutation of cancer genes in the mouse liver. Nature, 2014, 514(7522): 380-384.

 

26. Jia Chen, Brendan F. Miller and Anthony V. Furano*. Repair of naturally occurring mismatches can induce mutations in flanking DNA. Elife, 2014, 3: e02001.


(#: co-first author, *: corresponding author)

1. Chengfang Liu#, Sifan Cheng#, Junjie Zhu, Lina Zhou, Jia Chen*. A quick guide to evaluating prime editing efficiency in mammalian cells. Methods in Enzymology, 2025, 712: 419-436

 

2. Jiangchao Xiang#, Wenchao Xu#, Jing Wu#, Yaxin Luo, Bei Yang*, Jia Chen*. Nucleoside deaminases: the key players in base editing toolkit. Biophys Rep, 2023, 9(6): 325-337.

 

3. Jin-Soo Kim*, Jia Chen*. Base editing of organellar DNA with programmable deaminases. Nat Rev Mol Cell Biol, 2024, 25(1): 34-45.

 

4. Li Yang*, Jia Chen*. Expanding genome editing scopes with artificial intelligence. Sci Bull, 2023, 68(23): 2881-2883.

 

5. Caixia Gao* & Jia Chen*. CRISPR adventures in China. CRISPR J, 2021, 4: 304-306

 

6. Qiubing Chen, Ying Zhang* and Hao Yin*. Recent advances in chemical modifications of guide RNA, mRNA and donor template for CRISPR-mediated genome editing. Adv Drug Deliv Rev, 2021, 168: 246-258.

 

7. Li Yang* & Jia Chen*. A tale of two moieties: rapidly evolving CRISPR/Cas-based genome editing. Trends Biochem Sci, 2020, 45: 874-888

 

8. Li Yang*, Bei Yang* and Jia Chen*. One prime for all editing. Cell, 2019, 179: 1448-1450

 

9. Jia Chen*, Bei Yang* and Li Yang*. To BE or not to BE, that is the question. Nat Biotechnol, 2019, 37: 520-522

 

10. Bei Yang*, Li Yang* and Jia Chen*. Development and application of base editors. CRISPR J, 2019, 2: 91-104

 

11. Hong-Xia Zhang, Ying Zhang* and Hao Yin*. Genome editing with mRNA encoding ZFN, TALEN, and Cas9. Mol Ther, 2019, 27(4): 735-746.

 

12. Hao Yin*, Wen Xue* and Daniel G. Anderson*. CRISPR-Cas: a tool for cancer research and therapeutics. Nat Rev Clin Oncol, 2019, 16(5): 281-295.

 

13. Jia Chen, Weizhi Ji, Prashant Mali and April Pawluk. The future of genome editing. Cell, 2018, 173: 1311-1313

 

14. Bei Yang*, Xiaosa Li, Liqun Lei and Jia Chen*. APOBEC: from mutator to editor. J Genet Genomics, 2017, 44: 423-437


15. Hao Yin, Kevin J. Kauffman and Daniel G. Anderson*. Delivery technologies for genome editing. Nat Rev Drug Discov, 2017, 16(6): 387-399.

 

16. Hao Yin, Rosemary L Kanasty, Ahmed A Eltoukhy, Arturo J Vegas, J Robert Dorkin and Daniel G Anderson*. Non-viral vectors for gene-based therapy. Nat Rev Genet, 2014, 15(8): 541-555.

 

(#: co-first author, *: corresponding author)

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