Browsing by Subject "Base editing"

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    Base editing in humanized dystrophic mice
    (Elsevier, 2024-04-12) Zhang, Chen; Zhou, Yuan; Han, Renzhi; Pediatrics, School of Medicine
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    Liver-specific in vivo base editing of Angptl3 via AAV delivery efficiently lowers blood lipid levels in mice
    (BMC, 2023-06-15) Zuo, Yuanbojiao; Zhang, Chen; Zhou, Yuan; Li, Haiwen; Xiao, Weidong; Herzog, Roland W.; Xu, Jie; Zhang, Jifeng; Chen, Y. Eugene; Han, Renzhi; Pediatrics, School of Medicine
    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.