期刊
MOLECULAR THERAPY-NUCLEIC ACIDS
卷 1, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/mtna.2012.16
关键词
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资金
- Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation (NIBIO)
- Ministry of Health, Labor, and Welfare
- Japan Society for the Promotion of Science (JSPS) for Young Scientists
- Grants-in-Aid for Scientific Research [22591004] Funding Source: KAKEN
Recent findings in molecular biology implicate the involvement of proprotein convertase subtilisin/kexin type 9 ( PCSK9) in low-density lipoprotein receptor (LDLR) protein regulation. The cholesterol-lowering potential of anti-PCSK9 antisense oligonucleotides (AONs) modified with bridged nucleic acids (BNA-AONs) including 2', 4'-BNA (also called as locked nucleic acid (LNA)) and 2', 4'-BNANC chemistries were demonstrated both in vitro and in vivo. An in vitro transfection study revealed that all of the BNA-AONs induce dose-dependent reductions in PCSK9 messenger RNA (mRNA) levels concomitantly with increases in LDLR protein levels. BNA-AONs were administered to atherogenic diet-fed C57BL/6J mice twice weekly for 6 weeks; 2', 4'-BNAAON that targeted murine PCSK9 induced a dose-dependent reduction in hepatic PCSK9 mRNA and LDL cholesterol (LDL-C); the 43% reduction of serum LDL-C was achieved at a dose of 20 mg/kg/injection with only moderate increases in toxicological indicators. In addition, the serum high-density lipoprotein cholesterol (HDL-C) levels increased. These results support antisense inhibition of PCSK9 as a potential therapeutic approach. When compared with 2', 4'-BNA-AON, 2', 4'-BNANC-AON showed an earlier LDL-C-lowering effect and was more tolerable in mice. Our results validate the optimization of 2', 4'-BNANC-based anti-PCSK9 antisense molecules to produce a promising therapeutic agent for the treatment of hypercholesterolemia.
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