Antisense Oligonucleotide Inhibition of Apolipoprotein C-III Reduces Plasma Triglycerides in Rodents, Nonhuman Primates, and Humans

• Published in: Circulation research 2013-05, Vol.112 (11), p.1479-1490
• Main Authors: Graham, Mark J, Lee, Richard G, Bell, Thomas A, Fu, Wuxia, Mullick, Adam E, Alexander, Veronica J, Singleton, Walter, Viney, Nick, Geary, Richard, Su, John, Baker, Brenda F, Burkey, Jennifer, Crooke, Stanley T, Crooke, Rosanne M
• Format: Article
• Language: English
• Subjects: 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; Rats; Rats, Zucker; Receptors, LDL - genetics; Risk Factors; RNA, Messenger - metabolism; Triglycerides - blood
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/CIRCRESAHA.111.300367

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.