Extensive germline genome engineering in pigs

被引：123

作者：

Yue, Yanan ^{[1
]}

Xu, Weihong ^{[1
]}

Kan, Yinan ^{[2
]}

Zhao, Hong-Ye ^{[3
]}

Zhou, Yixuan ^{[1
]}

Song, Xiaobin ^{[1
]}

Wu, Jiajia ^{[1
]}

Xiong, Juan ^{[1
]}

Goswami, Dharmendra ^{[2
]}

Yang, Meng ^{[1
]}

Lamriben, Lydia ^{[2
]}

Xu, Mengyuan ^{[1
]}

Zhang, Qi ^{[1
]}

Luo, Yu ^{[1
]}

Guo, Jianxiong ^{[3
]}

Mao, Shengyi ^{[3
]}

Jiao, Deling ^{[3
]}

Nguyen, Tien Dat ^{[3
]}

Li, Zhuo ^{[3
]}

Layer, Jacob V. ^{[2
]}

Li, Mailin ^{[2
]}

Paragas, Violette ^{[2
]}

Youd, Michele E. ^{[2
]}

Sun, Zhongquan ^{[4
]}

Ding, Yuan ^{[4
]}

Wang, Weilin ^{[4
]}

Dou, Hongwei ^{[1
]}

Song, Lingling ^{[1
]}

Wang, Xueqiong ^{[1
]}

Le, Lei ^{[1
]}

Fang, Xin ^{[1
]}

George, Haydy ^{[2
]}

Anand, Ranjith ^{[2
]}

Wang, Shi Yun ^{[2
]}

Westlin, William F. ^{[2
]}

Guell, Marc ^{[5
]}

Markmann, James ^{[6
]}

Qin, Wenning ^{[2
]}

Gao, Yangbin ^{[1
]}

Wei, Hong-Jiang ^{[3
]}

Church, George M. ^{[7
]}

Yang, Luhan ^{[1
]}

机构：

[1] Qihan Bio Inc, Hangzhou, Peoples R China

[2] eGenesis Inc, Cambridge, MA USA

[3] Yunnan Agr Univ, Key Lab Anim Gene Editing & Anim Cloning Yunnan P, Kunming, Yunnan, Peoples R China

[4] Zhejiang Univ, Sch Med, Affiliated Hosp 2, Dept Hepatobiliary & Pancreat Surg, Hangzhou, Peoples R China

[5] Pompeu Fabra Univ, Dept Expt & Hlth Sci, Barcelona, Spain

[6] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA

[7] Harvard Med Sch, Dept Genet, Boston, MA 02115 USA

来源：

NATURE BIOMEDICAL ENGINEERING | 2021年 / 5卷 / 02期

关键词：

PORCINE ENDOTHELIAL-CELLS; FACTOR PATHWAY INHIBITOR; NUCLEAR TRANSFER; KNOCKOUT PIGS; CLONED PIGS; XENOTRANSPLANTATION; COAGULATION; EXPRESSION; SURVIVAL; BABOONS;

D O I：

10.1038/s41551-020-00613-9

中图分类号：

R318 [生物医学工程];

学科分类号：

0831 ;

摘要：

The clinical applicability of porcine xenotransplantation-a long-investigated alternative to the scarce availability of human organs for patients with organ failure-is limited by molecular incompatibilities between the immune systems of pigs and humans as well as by the risk of transmitting porcine endogenous retroviruses (PERVs). We recently showed the production of pigs with genomically inactivated PERVs. Here, using a combination of CRISPR-Cas9 and transposon technologies, we show that pigs with all PERVs inactivated can also be genetically engineered to eliminate three xenoantigens and to express nine human transgenes that enhance the pigs' immunological compatibility and blood-coagulation compatibility with humans. The engineered pigs exhibit normal physiology, fertility and germline transmission of the 13 genes and 42 alleles edited. Using in vitro assays, we show that cells from the engineered pigs are resistant to human humoral rejection, cell-mediated damage and pathogenesis associated with dysregulated coagulation. The extensive genome engineering of pigs for greater compatibility with the human immune system may eventually enable safe and effective porcine xenotransplantation. Pigs can be genetically modified to inactivate endogenous retroviruses and to display enhanced compatibility with the human immune system using a combination of CRISPR-Cas9 and transposon technologies.

引用

页码：134 / 143

页数：13

共 63 条

[1] Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer [J].