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
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.