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Published on: August 28, 2018
Inhibition of ApoCIII: the next PCSK9?
Sophie J Bernelot Moens1, Julian C van Capelleveen, Erik S G Stroes
1Department of Vascular Medicine, Academic Medical Center, Universiteit van Amsterdam, Amsterdam, the Netherlands.
Purpose Of Review:
Recent large Mendelian randomization studies associate loss-of-function mutations in apolipoprotein CIII (APOCIII) with low levels of triglycerides and decreased incidence of cardiovascular disease. With ample in-vitro and in-vivo evidence for a role of apoCIII in lipoprotein lipase-mediated triglyceride clearance and remnant removal, it is, thus, an attractive target for the treatment of hypertriglyceridemia and the prevention of cardiovascular disease. This review evaluates the current position of apoCIII in clinical practice and provides a glimpse into the future in terms of treatment options.
Recent Findings:
Two large Mendelian randomization studies have shown three identical loss-of-function mutations in APOCIII to be linked to favorable lipid profiles and lower incidence of coronary artery disease. A second-generation antisense oligonucleotide, which selectively inhibits apoCIII, was able to decrease serum apoCIII and triglyceride levels in rodents, nonhuman primates and humans.
Summary:
The central role of apoCIII in hypertriglyceridemia and cardiovascular disease was further cemented by recent findings and promising intervention data that showed the possibility of using antisense therapy to lower apoCIII and triglyceride levels. Currently, planned phase 3 trials should provide answers in regards to long-term efficacy and safety of this novel therapy.
Insights
Loss-of-function mutations in apolipoprotein CIII (APOCIII) are linked to reduced cardiovascular disease risk. Antisense therapy targeting APOCIII shows promise for treating hypertriglyceridemia and preventing heart disease.
Area of Science:
- Cardiovascular Medicine
- Genetics
- Pharmacology
Background:
- Apolipoprotein CIII (APOCIII) plays a key role in triglyceride metabolism and cardiovascular disease pathogenesis.
- Loss-of-function mutations in APOCIII are associated with lower triglyceride levels and reduced cardiovascular disease incidence.
Purpose of the Study:
- To review the current clinical significance of APOCIII in hypertriglyceridemia and cardiovascular disease.
- To explore future therapeutic strategies targeting APOCIII.
Main Methods:
- Evaluation of recent Mendelian randomization studies.
- Review of in-vitro and in-vivo evidence on APOCIII function.
- Assessment of antisense oligonucleotide therapy targeting APOCIII.
Main Results:
- Mendelian randomization studies identified three loss-of-function APOCIII mutations linked to favorable lipid profiles and lower coronary artery disease incidence.
- A second-generation antisense oligonucleotide effectively reduced serum APOCIII and triglyceride levels in preclinical models and humans.
Conclusions:
- Recent findings reinforce the central role of APOCIII in hypertriglyceridemia and cardiovascular disease.
- Antisense therapy targeting APOCIII presents a promising strategy for lowering triglycerides and potentially preventing cardiovascular events.
- Phase 3 trials are anticipated to determine the long-term efficacy and safety of this novel therapeutic approach.
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