Table of Contents:

ApoA-I Mimetics

A wealth of evidence indicates that plasma levels of high-density lipoprotein cholesterol (HDL-C) are inversely related to the risk of cardiovascular disease (CVD). Consequently, HDL-C has been considered a target for therapy in order to reduce the residual CVD burden that remains significant, even after application of current state-of-the-art medical interventions. In recent years, however, a number of clinical trials of therapeutic strategies that increase HDL-C levels failed to show the anticipated beneficial effect on CVD outcomes. As a result, attention has begun to shift toward strategies to improve HDL functionality, rather than levels of HDL-C per se. ApoA-I, the major protein component of HDL, is considered to play an important role in many of the antiatherogenic functions of HDL, most notably reverse cholesterol transport (RCT), and several therapies have been developed to mimic apoA-I function, including administration of apoA-I, mutated variants of apoA-I, and apoA-I mimetic peptides. Based on the potential anti-inflammatory effects, apoA-I mimetics hold promise not only as anti-atherosclerotic therapy but also in other therapeutic areas.

ApoA-I mimetics • ApoA-I analogues • ApoA-I infusion


The beneficial consequences of lowering low-density lipoprotein cholesterol (LDL-C) on cardiovascular (CVD) events have been unequivocally shown in numerous intervention studies. A plasma LDL-C reduction of 1.0 mmol/L has been shown to reduce the risk of major cardiovascular events by approximately 20 %, irrespective of baseline cholesterol or risk. Intensive LDL-C lowering is therefore advocated in most guidelines (Baigent et al. 2010). However, despite the efficiency of established therapies, the residual burden of disease remains substantial (Roger et al. 2012). Novel targets for therapy are therefore eagerly awaited in order to decrease the residual CVD risk.

A large number of epidemiological studies have shown that levels of highdensity lipoprotein cholesterol (HDL-C) are inversely associated with CVD risk. In fact, it has been calculated from these studies that a 1 mg/dL (0.03 mmol/L) increase in HDL-C would translate into a 2–3 % reduction of risk for subsequent coronary events (Gordon et al. 1989). Moreover, levels of HDL-C have been considered a stronger predictive factor of incident coronary heart disease than levels of LDL-C (Gordon et al. 1977). Even among patients who attain low levels of LDL-C while receiving LDL-C lowering therapy, levels of HDL-C remain predictive for subsequent CVD events (Barter et al. 2007; Jafri et al. 2010).

These epidemiological data do not infer a causal relation between levels of HDL-C and CVD risk. However, a number of antiatherogenic mechanisms have been ascribed to HDL. HDL has been shown to play a pivotal role in reverse cholesterol transport (RCT), a pathway by which cholesterol is transported from peripheral cells (e.g., macrophages within the vessel wall) to the liver for biliary excretion (Fielding and Fielding 1995). In addition, HDL has been shown to possess antioxidant, anti-inflammatory (Barter et al. 2004), antithrombotic (Mineo et al. 2006), and antiapoptotic properties (Suc et al. 1997).

HDL has been considered a target for therapy to lower CVD risk, based on both these epidemiological and biological arguments of atheroprotection. In recent years, a number of large clinical trial programs investigating the efficacy of drugs with an established effect on HDL-C levels have been terminated because of the inability to induce improvement in clinical outcomes. In addition, treatmentinduced changes in HDL-C were not associated with CVD risk after adjusting for LDL-C (Briel et al. 2009). Moreover, a number of common genetic variants in genes coding for proteins involved in HDL metabolism have been shown to alter levels of HDL-C without showing the anticipated effect on CVD risk (Haase et al. 2011; Voight et al. 2012). These findings challenge the concept that levels of circulating HDL-C are causally related to atherosclerosis, and assessment of HDL functionality has therefore been proposed to better reflect the therapeutic potential of therapies targeting HDL (deGoma et al. 2008).

Although levels of HDL-C alone may thus be a poor target for therapies, apolipoprotein A-1 (apoA-I) itself could in fact represent a promising target. ApoA-I is the major protein component of the HDL particle and considered to play a pivotal role in many of the antiatherogenic properties attributed to HDL. The role of apoA-I in the protection against atherosclerosis has been shown in a number of rodent studies. In low-density lipoprotein receptor (LDL-R) null mice, apoA-I deficiency was shown to result in increased atherosclerosis (Moore et al. 2003). Increased atherosclerotic lesion development was also seen in apoA-I knockout mice expressing human apolipoprotein B (apoB) when fed a Western diet (WD) (Voyiaziakis et al. 1998). Additional proof of the antiatherogenic role of apoA-I was derived from animal models of human apoA-I overexpression and in mice treated with apoA-I infusions, in which it was consistently shown that apoA-I provides protection against atherosclerotic lesion formation in proatherogenic animal models (Duverger et al. 1996; Miyazaki et al. 1995; Rubin et al. 1991). Moreover, mutations in the gene coding for apoA-I have been shown to alter CVD risk in humans. Most of the carriers of mutations in the apoA-I gene are characterized by low levels of HDL-C and an increased risk of CVD (Hovingh et al. 2004). ApoA-I is widely accepted as an attractive target for therapy based on the consistent data derived in animal and human studies. Several therapies have been developed that mimic apoA-I function, including administration of full length apoA-I, mutated variants of apoA-I, and apoA-I mimetic peptides.

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