Treatment and prevention of lipoprotein(a)-mediated cardiovascular disease: the emerging potential of RNA interference therapeutics

Abstract

Lipid- and lipoprotein-modifying therapies have expanded substantially in the last 25 years, resulting in reduction in the incidence of major adverse cardiovascular events. However, no specific lipoprotein(a) [Lp(a)]-targeting therapy has yet been shown to reduce cardiovascular disease risk. Many epidemiological and genetic studies have demonstrated that Lp(a) is an important genetically determined causal risk factor for coronary heart disease, aortic valve disease, stroke, heart failure, and peripheral vascular disease. Accordingly, the need for specific Lp(a)-lowering therapy has become a major public health priority. Approximately 20% of the global population (1.4 billion people) have elevated levels of Lp(a) associated with higher cardiovascular risk, though the threshold for determining 'high risk' is debated. Traditional lifestyle approaches to cardiovascular risk reduction are ineffective at lowering Lp(a). To address a lifelong risk factor unmodifiable by non-pharmacological means, Lp(a)-lowering therapy needs to be safe, highly effective, and tolerable for a patient population who will likely require several decades of treatment. N-acetylgalactosamine-conjugated gene silencing therapeutics, such as small interfering RNA (siRNA) and antisense oligonucleotide targeting LPA, are ideally suited for this application, offering a highly tissue- and target transcript-specific approach with the potential for safe and durable Lp(a) lowering with as few as three or four doses per year. In this review, we evaluate the causal role of Lp(a) across the cardiovascular disease spectrum, examine the role of established lipid-modifying therapies in lowering Lp(a), and focus on the anticipated role for siRNA therapeutics in treating and preventing Lp(a)-related disease.

Keywords: Cardiovascular disease; Lipoprotein(a); RNA interference; Therapeutics; Valvular disease.

Graphical abstract

Figure 1

Mechanism of action of Lp(a)-lowering siRNA therapy, and potential clinical benefits. GalNAc–siRNA drugs lower circulating Lp(a) concentrations via the mechanisms described in more detail in Figure 2. Evidence from observational and genetic epidemiological studies supports a role for Lp(a) lowering as a means of reducing the risk of several types of cardiovascular disease, including atherosclerotic in the coronary and peripheral circulations, valvular disease and heart failure. siRNA, small interfering RNA; ASGPR, asialoglycoprotein receptor; LPA, apolipoprotein(a) gene; Lp(a), lipoprotein(a).

Figure 2

A detailed overview of GalNAc–siRNA mechanism of action in the hepatocyte. A GalNAc–siRNA drug is administered subcutaneously and the GalNAc moiety binds the ASGPR on the hepatocyte cell membrane. The drug conjugate enters the cell via an endosomal mechanism, following which it escapes into the cytosol and the ASGPR recycles to the cell surface. The siRNA sense and antisense strands dissociate, and the antisense strand binds its target sequence in the LPA gene mRNA. Binding of the antisense strand induces degradation of LPA mRNA, preventing its translation into apo(a) and thereby reducing the synthesis of Lp(a). GalNAc, N-acetyl-galactosamine; ASGPR, asialoglycoprotein receptor; RISC, RNA-induced silencing complex; RNAi, RNA interference; AAA, gene transcript.