Antisense Oligonucleotide Inhibition of Apolipoprotein C-III Reduces Plasma Triglycerides in Rodents, Nonhuman Primates, and Humans
ABSTRACT Rationale: Elevated plasma triglyceride (TG) levels have been recognized as a risk factor for the development of coronary heart disease (CHD). Apolipoprotein C-III (apoC-III) represents both an independent risk factor and a key regulatory factor of plasma TG concentrations. Further, elevated apoC-III levels have been associated with metabolic syndrome and type 2 diabetes. 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 TG levels. Methods and Results: Rodent and human-specific second generation antisense oligonucleotides (ASOs) were identified and evaluated in preclinical models, including rats, mice, human apoC-III transgenic mice and non-human primates. We demonstrate the selective reduction of both apoC-III and TG in all preclinical pharmacological evaluations. We also show that inhibition of apoC-III was well tolerated and not associated with increased liver TG 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 TG 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 TG, two known risk factors for CV disease. This compelling pharmacological profile supports further clinical investigations in hypertriglyceridemic subjects.
SourceAvailable from: Punit P Seth[Show abstract] [Hide abstract]
ABSTRACT: The ss-siRNA activity in vivo requires a metabolically stable 5'-phosphate analog. In this report we used crystal structure of the 5'-phosphate binding pocket of Ago-2 bound with guide strand to design and synthesize ss-siRNAs containing various 5'-phosphate analogs. Our results indicate that the electronic and spatial orientation of the 5'-phosphate analog was critical for ss-siRNA activity. Chemically modified ss-siRNA targeting human apoC III mRNA demonstrated good potency for inhibiting ApoC III mRNA and protein in transgenic mice. Moreover, ApoC III ss-siRNAs were able to reduce the triglyceride and LDL cholesterol in transgenic mice demonstrating pharmacological effect of ss-siRNA. Our study provides guidance to develop surrogate phosphate analog for ss-siRNA and demonstrates that ss-siRNA provides an alternative strategy for therapeutic gene silencing. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.Nucleic Acids Research 03/2015; DOI:10.1093/nar/gkv162 · 8.81 Impact Factor
Article: APOC3: Triglycerides do matter.
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ABSTRACT: The purpose of this article is to summarize the recent epidemiological, basic science, and pharmaceutical research linking apolipoprotein C-III (apoC-III) with the development and treatment of cardiovascular disease (CVD). ApoC-III is an important emerging target linking hypertriglyceridemia with CVD. ApoC-III is a potent modulator of many established CVD risk factors, and is found on chylomicrons, very-low density lipoprotein, low-density lipoprotein, and high-density lipoprotein particles. Recent studies show that in humans, apoC-III levels are an independent risk factor for CVD, and its presence on lipoproteins may promote their atherogenicity. This year, two large-scale epidemiological studies have linked mutations in apoC-III with increased incidence of CVD and hypertriglyceridemia. ApoC-III raises plasma triglycerides through inhibition of lipoprotein lipase, stimulation of very-low density lipoprotein secretion, and is a novel factor in modulating intestinal triglyceride trafficking. ApoC-III also stimulates inflammatory processes in the vasculature and the pancreas. The combination of raising plasma triglycerides and independently stimulating inflammatory processes makes apoC-III a valuable target for reducing the residual CVD risk in patients already on statin therapy, or for whom triglycerides are poorly controlled. Clinical trials on apoC-III antisense oligonucleotides are in progress. ApoC-III is a potent direct modulator of established CVD risk factors: plasma triglycerides and inflammation. Recent findings show that changes in apoC-III levels are directly associated with changes in cardiovascular risk and the atherogenicity of the lipoproteins on which apoC-III resides. Emerging roles of apoC-III include a role in directing the atherogenicity of high-density lipoprotein, intestinal dietary triglyceride trafficking, and modulating pancreatic β-cell survival. The combination of these roles makes apoC-III an important therapeutic target for the management and prevention of CVD.