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.
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.
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.
"This provides strong human validation of APOC3 as a therapeutic target. A phase 1 trial of an antisense oligonucleotide against APOC3 has been reported showing dose-dependent reductions in TG with small increases in HDL-C . One small study of three patients with homozygous or compound heterozygous mutations in the LPL gene demonstrated that antisense inhibition of APOC3 lowered TGs by 50-80% , providing evidence that APOC3 also participates in an LPL-independent pathway of TG removal. "
[Show abstract][Hide abstract] ABSTRACT: Levels of high-density lipoprotein cholesterol (HDL-C) are inversely related to cardiovascular disease risk and HDL particles possess a variety of anti-atherosclerotic properties. However, several recent clinical trials aimed at raising HDL-C levels have failed to yield the expected improvement in clinical outcomes, highlighting the need for a better understanding of HDL particle function and metabolism. Human genetic studies have proven to be an outstanding source of insight regarding the biology of this complex lipoprotein class. In particular, the study of rare genetic disorders of HDL has identified a number of key players in HDL metabolism, some of which represent current or future therapeutic targets. More recently, genetic association studies have identified a large number of additional genes and proteins involved in HDL metabolism. The purpose of this review is to summarize progress in the study of HDL genetics and how these insights have contributed to our understanding of the metabolic pathways and function of HDL leading to opportunities for the long-elusive HDL-based therapies.
Progress in Lipid Research 01/2015; 85. DOI:10.1016/j.plipres.2015.01.001 · 10.02 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Increased plasma levels of C-reactive protein (CRP) are closely associated with cardiovascular diseases, but whether CRP is directly involved in the pathogenesis of atherosclerosis is still under debate. Many controversial and contradictory results using transgenic mice and rabbits have been published but it is also unclear whether CRP lowering can be used for the treatment of atherosclerosis. In the current study, we examined the effects of the rabbit CRP antisense oligonucleotides (ASO) on the development of atherosclerosis in WHHL rabbits. CRP ASO treatment led to a significant reduction of plasma CRP levels; however, both aortic and coronary atherosclerotic lesions were not significantly changed compared to those of control WHHL rabbits. These results suggest that inhibition of plasma CRP does not affect the development of atherosclerosis in WHHL rabbits.
Mediators of Inflammation 04/2014; 2014(8):979132. DOI:10.1155/2014/979132 · 3.24 Impact Factor
"As observed in preclinical studies, administration of ISIS 308401 led to significant dose-dependent reductions in apoC-III protein with concomitant reductions in plasma TG (−50 %) relative to baseline at the highest administered dose. Reductions in plasma apoC-III protein and TG were seen as early as 8 days after the initial dose . ISIS 308401 was generally well tolerated with no serious adverse events or early dosing terminations. "
[Show abstract][Hide abstract] ABSTRACT: Antisense oligonucleotides and small interfering RNAs, which suppress the translation of specific mRNA target proteins, are emerging as important therapeutic modalities for the treatment of cardiovascular disease. Over the last 25 years, the advances in all aspects of antisense technology, as well as a detailed understanding of the mechanism of action of antisense drugs, have enabled their use as therapeutic agents. These advancements culminated in the FDA approval of the first chronically administered cardiovascular antisense therapeutic, mipomersen, which targets hepatic apolipoprotein B mRNA. This review provides a brief history of antisense technology, highlights the progression of mipomersen from preclinical studies to multiple Phase III registration trials, and gives an update on the status of other cardiovascular antisense therapeutics currently in the clinic.
Journal of Cardiovascular Translational Research 07/2013; 6(6). DOI:10.1007/s12265-013-9495-7 · 3.02 Impact Factor
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