Targeting ANGPTL3 by GalNAc-conjugated siRNA ANGsiR10 lowers blood lipids with long-lasting and potent efficacy in mice and monkeys

Jue Wang; Wen Zheng; Shuquan Zheng; Ye Yuan; Wei Wen; Weiyi Cui; Lifang Xue; Xueting Sun; Haibao Shang; Hongyan Zhang; Rui-Ping Xiao; Shan Gao; Xiuqin Zhang

doi:10.1016/j.omtn.2022.11.023

Targeting ANGPTL3 by GalNAc-conjugated siRNA ANGsiR10 lowers blood lipids with long-lasting and potent efficacy in mice and monkeys

Mol Ther Nucleic Acids. 2022 Dec 5:31:68-77. doi: 10.1016/j.omtn.2022.11.023. eCollection 2023 Mar 14.

Authors

Jue Wang^{1

2}, Wen Zheng^{1

2}, Shuquan Zheng³, Ye Yuan^{1

2}, Wei Wen^{1

2

4}, Weiyi Cui^{1

2}, Lifang Xue⁵, Xueting Sun^{1

2}, Haibao Shang⁶, Hongyan Zhang³, Rui-Ping Xiao^{1

2

4

7}, Shan Gao³, Xiuqin Zhang^{1

2}

Affiliations

¹ Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing 100871, China.
² Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing 100871, China.
³ Suzhou Ribo Life Science Co., Ltd., Jiangsu 215300, China.
⁴ PKU-Nanjing Institute of Translational Medicine, Nanjing 211800, China.
⁵ Department of Ultrasonography, Peking University International Hospital, Beijing 102206, China.
⁶ Laboratory Animal Center, Peking University, Beijing 100871, China.
⁷ Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China.

Abstract

Angiopoietin-like protein 3 (ANGPTL3) is an important regulator of lipoproteins by inhibiting both lipoprotein and endothelial lipases. It has been intensively investigated as a drug target for the treatment of dyslipidemia. In the present study, a modified small interfering RNA (siRNA) conjugated with GalNAc ANGsiR10 was characterized by in vivo and in vitro studies for its effect on ANGPTL3 silencing, the reduction of plasma triglycerides (TGs), and cholesterol levels in disease models. The results showed that ANGsiR10 displayed a significant and long-lasting efficacy in reducing blood TG and cholesterol levels in both mice and monkeys. Remarkably, the maximal reductions of plasma TG levels in the hApoC3-Tg mice, a model with high TG levels, and the spontaneous dyslipidemia model of rhesus monkey were 96.3% and 67.7%, respectively, after a single dose of ANGsiR10, with long-lasting effects up to 15 weeks. The cholesterol levels were also reduced in response to treatment, especially the non-HDL-c level, without altering the ApoA/ApoB ratio. This study showed that ANGsiR10 is effective in treating dyslipidemia and is worth further development.

Keywords: ANGPTL3); MT: Oligonucleotides: Therapies and Applications; angiopoietin-like protein 3; cholesterol; dyslipidemia; siRNA; triglycerides.