Antisense Oligonucleotide Inhibition of Apolipoprotein C-III Reduces Plasma Triglycerides in Rodents, Nonhuman Primates, and Humans
Rationale: Elevated plasma triglyceride (TG) levels have been recognized as a risk factor for the development of coronary heart disease (CHD). Apolipoprotein C-III (apoC-III) represents both an independent risk factor and a key regulatory factor of plasma TG concentrations. Further, elevated apoC-III levels have been associated with metabolic syndrome and type 2 diabetes. 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 TG levels.
Methods and Results: Rodent and human-specific second generation antisense oligonucleotides (ASOs) were identified and evaluated in preclinical models, including rats, mice, human apoC-III transgenic mice and non-human primates. We demonstrate the selective reduction of both apoC-III and TG in all preclinical pharmacological evaluations. We also show that inhibition of apoC-III was well tolerated and not associated with increased liver TG 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 TG 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 TG, two known risk factors for CV disease. This compelling pharmacological profile supports further clinical investigations in hypertriglyceridemic subjects.
- antisense oligonucleotides
- lipids and lipoproteins
- clinical trial
- Received October 23, 2012.
- Revision received March 26, 2013.
- Accepted March 28, 2013.