Liver-specific in vivo base editing of Angptl3 via AAV delivery efficiently lowers blood lipid levels in mice

Cell & Bioscience

Research

Jie Xu¹  Y. Eugene Chen¹  Jifeng Zhang¹  Roland W. Herzog²  Weidong Xiao²  Yuan Zhou³  Renzhi Han³  Chen Zhang³  Haiwen Li³  Yuanbojiao Zuo⁴ 

[1] Center for Advanced Models for Translational Sciences and Therapeutics, University of Michigan Medical Center, Ann Arbor, MI, USA;Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, 46202, Indianapolis, IN, USA;Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, 46202, Indianapolis, IN, USA;Department of Surgery, The Ohio State University, 43210, Columbus, OH, USA;Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, 46202, Indianapolis, IN, USA;Department of Surgery, The Ohio State University, 43210, Columbus, OH, USA;Department of Pediatrics, Third Xiangya Hospital of Central South University, 410013, Changsha, Hunan, P.R. China;

关键词: ANGPTL3;    Cholesterol;    Base editing;    Base editor;    Cardiovascular disease;    CVD;    Triglyceride;   

DOI  :  10.1186/s13578-023-01036-0

 received in 2023-02-17, accepted in 2023-04-18,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundGene editing has emerged as an exciting therapeutic development platform for numerous genetic and nongenetic diseases. Targeting lipid-modulating genes such as angiopoietin-related protein 3 (ANGPTL3) with gene editing offers hope for a permanent solution to lower cardiovascular disease risks associated with hypercholesterolemia.ResultsIn this study, we developed a hepatocyte-specific base editing therapeutic approach delivered by dual adeno-associated virus (AAV) to enable hepatocyte-specific targeting of Angptl3 to lower blood lipid levels. Systemic AAV9-mediated delivery of AncBE4max, a cytosine base editor (CBE), targeting mouse Angptl3 resulted in the installation of a premature stop codon in Angptl3 with an average efficiency of 63.3 ± 2.3% in the bulk liver tissue. A near-complete knockout of the ANGPTL3 protein in the circulation were observed within 2–4 weeks following AAV administration. Furthermore, the serum levels of triglyceride (TG) and total cholesterol (TC) were decreased by approximately 58% and 61%, respectively, at 4 weeks after treatment.ConclusionsThese results highlight the promise of liver-targeted Angptl3 base editing for blood lipid control.

【 授权许可】

CC BY   
© The Author(s) 2023

【 图 表 】

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