Details

Autor(en) / Beteiligte

• 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

Titel

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

Ist Teil von

• Circulation research, 2013-05, Vol.112 (11), p.1479-1490

Ort / Verlag

United States: American Heart Association, Inc

Erscheinungsjahr

2013

Quelle

Elektronische Zeitschriftenbibliothek (Open access)

Beschreibungen/Notizen

• 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.