RGD Reference Report - Antisense oligonucleotide inhibition of apolipoprotein C-III reduces plasma triglycerides in rodents, nonhuman primates, and humans. - Rat Genome Database

Send us a Message



Submit Data |  Help |  Video Tutorials |  News |  Publications |  Download |  REST API |  Citing RGD |  Contact   

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

Authors: Graham, MJ  Lee, RG  Bell TA, 3RD  Fu, W  Mullick, AE  Alexander, VJ  Singleton, W  Viney, N  Geary, R  Su, J  Baker, BF  Burkey, J  Crooke, ST  Crooke, RM 
Citation: Graham MJ, etal., Circ Res. 2013 May 24;112(11):1479-90. doi: 10.1161/CIRCRESAHA.111.300367. Epub 2013 Mar 29.
RGD ID: 10054091
Pubmed: PMID:23542898   (View Abstract at PubMed)
DOI: DOI:10.1161/CIRCRESAHA.111.300367   (Journal Full-text)

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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
familial hyperlipidemia treatmentISOApoc3 (Mus musculus)10054091; 10054091 RGD 
familial hyperlipidemia treatmentIMP 10054091 RGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
positive regulation of triglyceride biosynthetic process  IMP 10054091 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Apoc3  (apolipoprotein C3)

Genes (Mus musculus)
Apoc3  (apolipoprotein C-III)

Genes (Homo sapiens)
APOC3  (apolipoprotein C3)


Additional Information