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Cholesterol-lowering Action of BNA-based Antisense Oligonucleotides Targeting PCSK9 in Atherogenic Diet-induced

Tsuyoshi Yamamoto1, Mariko Harada-Shiba, Moeka Nakatani

  • 11] Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Japan [2] Department of Molecular Innovation in Lipidology, National Cerebral and Cardiovascular Center Research Institute, Suita, Japan.

Molecular Therapy. Nucleic Acids
|January 25, 2013
PubMed

Insights

New bridged nucleic acid antisense oligonucleotides (BNA-AONs) effectively lower LDL cholesterol by targeting PCSK9. The 2

Area of Science:

  • Molecular Biology
  • Genetics
  • Pharmacology

Background:

  • Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a key role in regulating low-density lipoprotein receptor (LDLR) levels.
  • Dysregulation of PCSK9 is implicated in hypercholesterolemia, a condition characterized by high levels of LDL cholesterol.
  • Antisense oligonucleotides (AONs) offer a potential therapeutic strategy for modulating gene expression.

Purpose of the Study:

  • To evaluate the cholesterol-lowering efficacy and safety of novel anti-PCSK9 antisense oligonucleotides (AONs) modified with bridged nucleic acids (BNA-AONs).
  • To compare the performance of different BNA-AON chemistries, specifically 2',4'-BNA (locked nucleic acid, LNA) and 2',4'-BNA(NC).

Main Methods:

  • In vitro studies involving cell transfection to assess the impact of BNA-AONs on PCSK9 mRNA and LDLR protein levels.
  • In vivo studies using atherogenic diet-fed C57BL/6J mice treated with BNA-AONs over a 6-week period.
  • Dose-response assessments and evaluation of toxicological indicators and lipid profiles (LDL-C, HDL-C).

Main Results:

  • All tested BNA-AONs demonstrated dose-dependent reductions in PCSK9 mRNA and increases in LDLR protein in vitro.
  • In vivo, a 2',4'-BNA-AON targeting murine PCSK9 significantly reduced hepatic PCSK9 mRNA and LDL cholesterol (LDL-C), achieving a 43% reduction at 20 mg/kg/injection.
  • The 2',4'-BNA(NC)-AON exhibited a faster LDL-C lowering effect and improved tolerability compared to 2',4'-BNA-AON, with observed increases in HDL-C.

Conclusions:

  • Antisense inhibition of PCSK9 using BNA-AONs is a viable therapeutic strategy for managing hypercholesterolemia.
  • The 2',4'-BNA(NC) chemistry represents a promising advancement, offering enhanced efficacy and tolerability for anti-PCSK9 therapeutic development.
  • Optimized 2',4'-BNA(NC)-based antisense molecules hold potential as effective agents for treating high cholesterol levels.

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