title: Antisense oligonucleotide inhibition of apolipoprotein C-III reduces plasma triglycerides in rodents, nonhuman primates, and humans.
abstract: BACKGROUND
  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.
  
  
  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.
authors.affiliation: Isis Pharmaceuticals, Carlsbad, CA 92010, USA. mgraham@isisph.com
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Graham
authors.forename: Richard G
authors.initials: RG
authors.lastname: Lee
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Bell
authors.forename: Wuxia
authors.initials: W
authors.lastname: Fu
authors.forename: Adam E
authors.initials: AE
authors.lastname: Mullick
authors.forename: Veronica J
authors.initials: VJ
authors.lastname: Alexander
authors.forename: Walter
authors.initials: W
authors.lastname: Singleton
authors.forename: Nick
authors.initials: N
authors.lastname: Viney
authors.forename: Richard
authors.initials: R
authors.lastname: Geary
authors.forename: John
authors.initials: J
authors.lastname: Su
authors.forename: Brenda F
authors.initials: BF
authors.lastname: Baker
authors.forename: Jennifer
authors.initials: J
authors.lastname: Burkey
authors.forename: Stanley T
authors.initials: ST
authors.lastname: Crooke
authors.forename: Rosanne M
authors.initials: RM
authors.lastname: Crooke
mesh_terms: D000818:Animals; D053305:Apolipoprotein C-III / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D004311:Double-Blind Method; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D015228:Hypertriglyceridemia / Q000097:blood / Q000453:epidemiology / Q000235:genetics / Q000628:therapy*; D008252:Macaca fascicularis; D008253:Macaca mulatta; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009841:Oligonucleotides / Q000493:pharmacokinetics / Q000494:pharmacology*; D016376:Oligonucleotides, Antisense / Q000493:pharmacokinetics / Q000494:pharmacology*; D010919:Placebos; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011924:Rats, Zucker; D011973:Receptors, LDL / Q000235:genetics; D012307:Risk Factors; D014280:Triglycerides / Q000097:blood*
chemical_list: D053305:Apolipoprotein C-III; C000593612:ISIS 304801; D009841:Oligonucleotides; D016376:Oligonucleotides, Antisense; D010919:Placebos; D012333:RNA, Messenger; D011973:Receptors, LDL; D014280:Triglycerides
keywords: antisense oligonucleotides; apolipoprotein; apolipoprotein C-III; clinical trial; lipids and lipoproteins; pharmacology; triglycerides