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Antisense Oligonucleotide Inhibition of Apolipoprotein C-III Reduces Plasma Triglycerides in Rodents, Nonhuman Primates, and Humans
Abstract
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.
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“The data remain inconclusive and the clinical efficacy of omega-3 fatty acids appears to be related to non-lipid effects [330,331].”
From 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk (2019) · cites this paper as [330]
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“ApoCIII has been identified as a new potential therapeutic target that is currently being studied, but whether it has a role in clinical practice is unknown and its measurements on a routine basis are not encouraged. 108”
From 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias (2016) · cites this paper as [108]
In the citing paper
“ApoCIII has been identified as a new potential therapeutic target that is currently being studied, but whether it has a role in clinical practice is unknown and its measurements on a routine basis are not encouraged.108”
From 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias (2016) · cites this paper as [108]
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Metadata
- Authors
- Graham, M. J., Lee, R. G., Bell, T. A., Fu, W., Mullick, A. E., Alexander, V. J., Singleton, W., Viney, N., Geary, R., Su, J., Baker, B. F., Burkey, J., Crooke, S. T., & Crooke, R. M.
- Affiliations
- Ionis Pharmaceuticals (United States) (US)
- Corresponding author
- Graham, Mark J.
- Lee, Richard G.
- ORCID
- Venue
- Circulation Research
- Published
- 2013-05-24
- Volume
- 112
- Issue
- 11
- Pages
- 1479-1490
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- OpenAlex
- W2170210469
- Cited by
- 377
- References
- 71
- Citations by year
- 2026: 16 · 2025: 14 · 2024: 15 · 2023: 17 · 2022: 31 · 2021: 19 · 2020: 41 · 2019: 31 · 2018: 29 · 2017: 25 · 2016: 45 · 2015: 41 · 2014: 39 · 2013: 12
- FWCI
- 31.05
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Circulation Research (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
- Keywords
- apolipoprotein C-III, antisense oligonucleotides, plasma triglycerides, hypertriglyceridemia, triglyceride-lowering therapy, cardiovascular risk factors, type 2 diabetes, metabolic syndrome, hepatotoxicity, non-human primates
- MeSH terms
- Animals, Double-Blind Method, Humans, Macaca fascicularis, Macaca mulatta, Mice, Inbred C57BL, Oligonucleotides, Placebos, Rats, Zucker, Receptors, LDL, Risk Factors, RNA, Messenger, Triglycerides, Hypertriglyceridemia, Genetic Therapy, Oligonucleotides, Antisense, Mice, Knockout, Mice, Rats, Apolipoprotein C-III
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