APOCIII- a promising new therapeutic targetLiterature - Moens SJ et al., Curr Opin Lipidol. 2014 - Curr Opin Lipidol. 2014 Sep 24
Inhibition of ApoCIII: the next PCSK9?
Moens SJ, van Capelleveen JC, Stroes ES
Curr Opin Lipidol. 2014 Sep 24
Loss-of-function mutations in apolipoprotein CIII (APOCIII) have recently been described to be associated with low levels of triglycerides (TGs) and a lower cardiovascular disease (CVD) risk. A parallel was drawn with PCSK9, emphasizing the importance of naturally occurring low-of-function mutations in the development of novel therapeutic agents. The identification of PCSK9 in 2003 has very rapidly translated into development of a therapeutic antibody against PCSK9 and its testing in currently ongoing phase III studies. APOCIII may also be a target that can benefit from the development of new techniques, including silencing RNA and novel human antibody technology.
Triglyceride levels and cardiovascular diseaseHypertriglyceridaemia (fasting plasma TG > 200 mg/dl or >2.2 mmol/l) has been recognised as an important therapeutic target. Also nonfasting triglycerides are considered a target, since postprandial remnant lipoproteins are thought to contribute to atherogenesis. Since high TG levels often go together with low HDL-c levels, the respective contributions of TG and HDL to CVD risk were hard to distinguish. Recent Mendelian randomisation studies suggest a direct causal association between TG levels and CVD risk, independent of HDL levels.
Current treatmentFew effective therapeutic agents are available to treat hypertriglyceridaemia. The combination of diet, exercise and drugs are recommended as the first-line treatment. Despite the absence of solid outcome data, fibrates are considered first-line treatment for patients who are at risk of developing TG-induced pancreatitis. Similarly, nicotinic acid are used to lower TG levels. Although outcome trials have not shown a consistent CV benefit.
Several new agents that target molecular pathways in TG metabolism are currently in different stages of development.
The enzyme acyl-CoA: diaglycerolacyltransferase (DGAT) reassembles the residues of hydrolysed TGs derived from dietary sources in enterocytes. In murine studies, targeting DGAT1 reduced chylomicron formation and lowered postprandial TG levels. In humans, 3 weeks of treatment with a DGAT2 inhibitor lowered mean fasting TG levels.
Microsomal triglyceride transfer protein (MTTP) is responsible for the lipidation of apoB48 with newly formed TGs, as a first step to chylomicron formation. Inhibition of MTTP was recently shown to effectively lower LDL-c and TG levels, but it yields gastro-intestinal side-effects and increased liver fat content.
Lipoprotein lipase (LPL) is the key enzyme responsible for lipolysis in the systemic circulation. In LPL-deficiency-based hypertriglyceridaemia, LPL gene therapy effectively lowered plasma TG levels. Although fasting plasma TG levels still returned to baseline after a few months, chylomicron clearance after a meal did improve, which reduced the risk of pancreatitis (alipogene tiparvovec has received EMA approval).
APOCIII is a negative regulator of LPL activity, and is now being explored as a target for TG lowering.
Apolipoprotein CIII and cardiovascular diseaseAPOCIII is mainly present on apoB-containing TG-rich particles (chylomicrons and VLDL), and less on HDL particles. It potently inhibits LPL-mediated lipolysis, and it may facilitate hepatic VLDL assembly and secretion. The AHA has recently stated that TGs may be atherogenic through their association with apoCIII, which is supported by studies showing direct associations between APOCIII levels and CVD. In addition, persons with heterozygous mutations or polymorphisms in APOC3 have a favourable lipid profile and improved CV health.
Two independent Mendelian randomisation research efforts have recently identified three loss-of-function variants in the APOCIII gene, which were associated with around 40% lower TG levels and over 20% increased HDL-c and 16% lower LDL-c. Risk of coronary heart disease was reduced in carriers of the APOCIII mutations. These studies, in combination with in vitro and murine studies, strongly suggest a causal association between apoCIII levels and CVD, thus providing further support for APOCIII as a therapeutic target.
Impact of apolipoprotein CIII on proinflammatory pathwaysAPOCIII activates peripheral monocytes by increasing the expression of β-integrin, which allows monocytes to adhere to the endothelium and migrate to the vascular intima. In vitro and in vivo studies have shown that APOCIII can activate vascular adhesion molecule-1 in nonactivated endothelial cells; an important step in the recruitment of circulating monocytes. This suggested interaction of APOCIII with vascular inflammation adds to its attractiveness as a target.
Both rodent-specific and human-specific inhibitors of APOCIII have been shown to selectively inhibit APOCIII and TG levels in rodents, non-human primates and healthy volunteers.
Preclinical work/antisense oligonucleotide
Clinical trialsAPOCIII antisense therapy has been tested in phase II studies in a broad range of patient groups with moderately to severely elevated TG levels. Unpublished data show that ISIS-ApoCIIIRx effectively lowered APOCIII and TG levels in diabetic patients and in patients with severely elevated TG levels, in a 13 week long blinded randomised study, in comparison to placebo. Phase III clinical trials have been announced, focussing on patients with familial chylomicronemia syndrome. Although a good safety profile was observed in phase I and II studies, these trials should specifically establish the effect of APOCIII on liver fat, as it could theoretically result in TG accumulation in the liver, due to its role in VLDL secretion.
ConclusionThe results from the first phase III trial will mostly show the value of APOCIII inhibition in hypertriglyceridaemic patients. Considering the role of APOCIII in processes involved in the development and progression of atherosclerotic plaques, later research may also show its value for treatment of CVD per se.
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