Cell & Bioscience | |
Liver-specific in vivo base editing of Angptl3 via AAV delivery efficiently lowers blood lipid levels in mice | |
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
【 预 览 】
Files | Size | Format | View |
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RO202309070286366ZK.pdf | 2449KB | download | |
MediaObjects/12951_2023_1942_MOESM3_ESM.tiff | 5102KB | Other | download |
Fig. 1 | 3122KB | Image | download |
Fig. 7 | 49KB | Image | download |
42004_2023_911_Article_IEq62.gif | 1KB | Image | download |
MediaObjects/42004_2022_674_MOESM1_ESM.pdf | 6815KB | download | |
Fig. 12 | 1298KB | Image | download |
【 图 表 】
Fig. 12
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Fig. 7
Fig. 1
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