Antisense oligonucleotide inhibition of apolipoprotein C-III reduces plasma triglycerides in rodents, nonhuman primates, and humans

Circ Res. 2013 May 24;112(11):1479-90. doi: 10.1161/CIRCRESAHA.111.300367. Epub 2013 Mar 29.

Abstract

Rationale: Elevated plasma triglyceride levels have been recognized as a risk factor for the development of coronary heart disease. Apolipoprotein C-III (apoC-III) represents both an independent risk factor and a key regulatory factor of plasma triglyceride concentrations. Furthermore, elevated apoC-III levels have been associated with metabolic syndrome and type 2 diabetes mellitus. To date, no selective apoC-III therapeutic agent has been evaluated in the clinic.

Objective: To test the hypothesis that selective inhibition of apoC-III with antisense drugs in preclinical models and in healthy volunteers would reduce plasma apoC-III and triglyceride levels.

Methods and results: Rodent- and human-specific second-generation antisense oligonucleotides were identified and evaluated in preclinical models, including rats, mice, human apoC-III transgenic mice, and nonhuman primates. We demonstrated the selective reduction of both apoC-III and triglyceride in all preclinical pharmacological evaluations. We also showed that inhibition of apoC-III was well tolerated and not associated with increased liver triglyceride deposition or hepatotoxicity. A double-blind, placebo-controlled, phase I clinical study was performed in healthy subjects. Administration of the human apoC-III antisense drug resulted in dose-dependent reductions in plasma apoC-III, concomitant lowering of triglyceride levels, and produced no clinically meaningful signals in the safety evaluations.

Conclusions: Antisense inhibition of apoC-III in preclinical models and in a phase I clinical trial with healthy subjects produced potent, selective reductions in plasma apoC-III and triglyceride, 2 known risk factors for cardiovascular disease. This compelling pharmacological profile supports further clinical investigations in hypertriglyceridemic subjects.

Keywords: antisense oligonucleotides; apolipoprotein; apolipoprotein C-III; clinical trial; lipids and lipoproteins; pharmacology; triglycerides.

Publication types

  • Clinical Trial, Phase I
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apolipoprotein C-III / antagonists & inhibitors*
  • Apolipoprotein C-III / genetics*
  • Apolipoprotein C-III / metabolism
  • Double-Blind Method
  • Genetic Therapy / methods*
  • Humans
  • Hypertriglyceridemia / blood
  • Hypertriglyceridemia / epidemiology
  • Hypertriglyceridemia / genetics
  • Hypertriglyceridemia / therapy*
  • Macaca fascicularis
  • Macaca mulatta
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Oligonucleotides / pharmacokinetics
  • Oligonucleotides / pharmacology*
  • Oligonucleotides, Antisense / pharmacokinetics
  • Oligonucleotides, Antisense / pharmacology*
  • Placebos
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Zucker
  • Receptors, LDL / genetics
  • Risk Factors
  • Triglycerides / blood*

Substances

  • Apolipoprotein C-III
  • ISIS 304801
  • Oligonucleotides
  • Oligonucleotides, Antisense
  • Placebos
  • RNA, Messenger
  • Receptors, LDL
  • Triglycerides