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 lipoprotein(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 lipoprotein(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 (GalNAc)-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 lipoprotein(a) lowering with as few as three or four doses per year. In this review, we evaluate the causal role of lipoprotein(a) across the cardiovascular disease spectrum, examine the role of established lipid modifying therapies in lowering lipoprotein(a), and focus on the anticipated role for siRNA therapeutics in treating and preventing lipoprotein(a)-related disease.

Lipoprotein(a): a risk factor for atherosclerosis and an emerging therapeutic target

“…Cholesteryl ester transfer protein inhibitors, which interfere with hepatic secretion of apoB-containing lipoproteins, lower Lp(a) by 25%–40% but a clinical benefit has not been demonstrated 29…”

“…Olpasiran and SLN360, both siRNAs, are further Lp(a)-lowering medications under development. Available data (~90% Lp(a) reduction) on these drugs are mainly derived from animal models 29…”

Elevated Lipoprotein(a): Background, Current Insights and Future Potential Therapies

“…These have just started phase 1 and 2 studies in man. 112 Structural work on the binding properties of Kringle domains has led to the development of AZ-005 which inhibits the function of K-IV10 domain and this small molecule inhibitor may proceed to human trials. 113 …”

Update on MicroRNA-based Treatment Strategies

“…Dennoch sind die Erfolgsaussichten für die Entwicklung von auf miRNA-basierten Medikamenten sehr vielversprechend. [10][11][12]. Especially the recent boost of vaccination strategies during the Covid-19 pandemic is likely to substantially accelerate the development of treatment formulations and indications derived from the upcoming "RNA world".…”

“…Medikamente für die Blutfettsenkung und Impfstoffe für die Covid-19 Impfung, s. auch Haupt-Text). Mehrere Substanzen befinden sich in der präklinischen und klinischen Entwicklung (10)(11)(12). Der aktuell im Zuge der Corona-Pandemie eingetretene Schub der Entwicklung RNA-basierter Strategien für die Impfung wird mit hoher Wahrscheinlichkeit die Entwicklung von anderen Wirkstoffen aus der so genannten "RNA-Welt" erheblich beschleunigen.…”