cholesterol-lowering action of bna-based antisense oligonucleotides targeting pcsk9 in atherogenic diet-induced hypercholesterolemic mice
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ID: 193170
2012
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Abstract
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′-BNA-AON 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.
| Reference Key |
yamamoto2012molecularcholesterol-lowering
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| Authors | ;Tsuyoshi Yamamoto;Mariko Harada-Shiba;Moeka Nakatani;Shunsuke Wada;Hidenori Yasuhara;Keisuke Narukawa;Kiyomi Sasaki;Masa-Aki Shibata;Hidetaka Torigoe;Tetsuji Yamaoka;Takeshi Imanishi;Satoshi Obika |
| Journal | coordination chemistry reviews |
| Year | 2012 |
| DOI |
10.1038/mtna.2012.16
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| URL | |
| Keywords |
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