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

Yuanbojiao Zuo; Chen Zhang; Yuan Zhou; Haiwen Li; Weidong Xiao; Roland W Herzog; Jie Xu; Jifeng Zhang; Y Eugene Chen; Renzhi Han

doi:10.1186/s13578-023-01036-0

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

Cell Biosci. 2023 Jun 15;13(1):109. doi: 10.1186/s13578-023-01036-0.

Authors

Yuanbojiao Zuo^{1

2

3}, Chen Zhang^{1

2}, Yuan Zhou^{1

2}, Haiwen Li^{1

2}, Weidong Xiao¹, Roland W Herzog¹, Jie Xu⁴, Jifeng Zhang⁴, Y Eugene Chen⁴, Renzhi Han^{5

6}

Affiliations

¹ Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
² Department of Surgery, The Ohio State University, Columbus, OH, 43210, USA.
³ Department of Pediatrics, Third Xiangya Hospital of Central South University, Changsha, 410013, Hunan, P.R. China.
⁴ Center for Advanced Models for Translational Sciences and Therapeutics, University of Michigan Medical Center, Ann Arbor, MI, USA.
⁵ Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, 46202, USA. rh11@iu.edu.
⁶ Department of Surgery, The Ohio State University, Columbus, OH, 43210, USA. rh11@iu.edu.

Abstract

Background: Gene 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.

Results: In 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.

Conclusions: These results highlight the promise of liver-targeted Angptl3 base editing for blood lipid control.

Keywords: ANGPTL3; Base editing; Base editor; CVD; Cardiovascular disease; Cholesterol; Triglyceride.

Abstract

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