The Promise and Challenges of RNA-targeted Therapeutics in Preventive Cardiology

Benoit J. Arsenault

Disclosures

Eur Heart J. 2022;43(7):550-552. 

Despite landmark achievements made in the past 50 years to understand, treat, and prevent atherosclerotic cardiovascular diseases (ACVD), preventing heart attacks and strokes in high-risk patients still remains very challenging for clinicians. Our pharmacological arsenal of preventive therapies like statins and medicines targeting high blood pressure are effective in reducing the burden of ACVD, but they leave behind an important 'residual risk'. Over the years, it has become increasingly recognized that our sedentary lifestyle and toxic food environment, our exposure to chronic stress, tobacco smoke and poor air quality contribute greatly to this so-called residual risk. The rise in the prevalence of cardiometabolic disease such as type 2 diabetes (T2D) and non-alcoholic fatty liver diseases (NAFLD) combined with systemic inflammation have also been shown to increase ACVD risk burden in the general population. From a pathophysiological standpoint, apolipoprotein B (apoB)-containing lipoproteins are the major drivers of ACVD and we have yet to find the threshold at which further lowering blood levels of apoB-containing lipoproteins is not beneficial for cardiovascular health.[1] In the majority of patients, the most abundant atherogenic apoB-containing lipoproteins in the bloodstream include triglyceride-rich lipoproteins such as very-low-density lipoproteins (VLDLs) and their remnants, low-density lipoproteins (LDLs) and lipoprotein(a) (Lp[a]). ApoB-containing lipoproteins are the major culprit in ACVD and since most clinicians have limited options to target factors contributing to ACVD residual risk, developing therapies that will further reduce all apoB-containing lipoproteins is likely to represent the most effective and achievable strategy to prevent ACVD in high-risk patients.

Seminal genetic discoveries made in the past two decades have fostered our understanding of the factors regulating apoB-containing lipoprotein levels and have identified a handful of blood proteins that cause ACVD through the modulation of apoB-containing lipoprotein concentrations.[2] Proprotein convertase subtilisin/kexin-9 (PCSK9) is a classic example of the genetic discovery of a circulating protein that regulates circulating LDL cholesterol levels, predicts ACVD risk, and if targeted by monoclonal antibodies, lowers LDL cholesterol levels and prevents ACVD.[3] Other examples of molecules that were genetically validated and regulate blood levels of other apoB-containing lipoproteins include apo(a), the apolipoprotein contributing to Lp(a) levels, apoC-III, a protein regulating triglyceride levels and angiopoietin-like 3 (ANGPTL3), a protein that regulates both triglyceride and LDL cholesterol levels. Developing small molecules against these proteins that could be administrated orally is very challenging and would be unhelpful in the case of Lp(a), apoC-III, and ANGPTL3 since these proteins have no enzymatic activity. Monoclonal antibodies targeted against PCSK9 and ANGPTL3 have been shown to have positive effects on lipoprotein-lipid levels. The clinical translation of these molecule, however, has been hampered by the fact that the initial cost of these monoclonal antibodies was prohibitive and that very large amounts of antibodies against apo(a) or apoC-III would be needed to efficiently reduce Lp(a) levels or triglycerides, respectively.

RNA therapeutics represent an entirely novel platform to inhibit or 'silence' the expression of almost any disease-causing gene. Both double-stranded small inhibiting RNAs (siRNAs) and single-stranded antisense oligonucleotide (ASO) technologies aim at degrading mRNA transcripts of interest thereby blocking protein synthesis.[4] While the antisense strand of siRNAs employs an RNA-induced silencing complex mechanism that operates in the cytosol, ASOs utilize a single-stranded RNase H mechanism that operates in the nucleus and in the cytosol. A noteworthy advantage of RNA therapeutics under development for the prevention of ACVD is that their genetic targets are almost exclusively expressed in the liver. The liver is an organ of choice for the efficient and specific delivery of RNA therapeutics. Both siRNAs and ASOs have been chemically engineered to efficiently bind asialoglycoprotein receptors, which are expressed at the surface of hepatocytes, but not at the surface of other cell types. Consequently, the concentrations of drugs can be lowered to provide optimal efficiency while reducing drug concentrations in other organs (Figure 1).

Figure 1.

RNA-based therapies targeting apolipoprotein B-containing lipoprotein concentrations. Hepatic genetic targets of small inhibiting RNA or antisense oligonucleotides (ASO) reduce the production of proteins influencing lipoprotein concentrations that contribute to the development of atherosclerotic cardiovascular diseases. RNA-based therapies targeting APOC3 or ANGPTL3 decrease triglyceride-rich lipoprotein levels (both) or low-density lipoprotein (LDL) cholesterol levels (ANGPTL3 only) while others targeting of PCKS9 reduce LDL cholesterol levels. The LPA gene targeted by an ASO would reduce Lp(a) levels. Created with BioRender.com.

Results of phase 2 trials revealed that an siRNA targeting PCSK9 and an ASO targeting ANGPTL3 efficiently reduced LDL cholesterol levels (and triglyceride levels in the case of the ANGPTL3 ASO)[5,6] that an ASO targeting APOC3 efficiently reduced triglyceride levels[7] and that an ASO targeting the LPA gene efficiently reduced Lp(a) levels.[8] There are, however, no phase 3 cardiovascular outcome trials' (CVOTs) data providing evidence that these RNA-based therapies ultimately reduce cardiovascular outcomes. CVOTs documenting the effect of some of these therapies are currently underway (NCT04023552 and NCT03705234). The majority of these drug targets have been 'genetically validated', meaning that genetic variants providing loss of function in the protein or variants reducing hepatic genetic expression of these genes have been linked with a lower risk of ACVD. New liver-expressed genes causing cardiovascular diseases with few therapeutic options available such as calcific aortic stenosis, stroke, heart failure, and peripheral artery disease are being discovered at an unprecedented pace. Given that RNA-based therapeutics can now be synthesized and developed using only the knowledge of the genetic sequence of disease-causing genes, the future of RNA-based therapeutics in the field of preventive cardiology or vascular medicine is promising. In line with the unprecedented rise in the worldwide prevalence of cardiometabolic disease and the fact that several liver-expressed genes play a central role in not only ACVD but also NAFLD and T2D, RNA therapeutics targeting the liver may be developed for a broader range of chronic diseases.

Messenger RNA-based vaccines have already saved countless lives and helped several countries around the world manage the COVID-19 pandemic. The technology behind RNA-based therapies has been under development for more than a quarter of a century. Messenger RNA-based vaccines have been developed using only the genetic sequence of SARS-CoV-2, the virus causing COVID-19 and have been massively produced within only a few months. The rapid development of these agents and the ongoing international effort to ensure that the worldwide population can benefit from these therapies set an important precedent that should pave the way for equally ambitious international programmes tackling the ongoing pandemic of ACVD. If RNA-targeted therapeutics aiming at reducing apoB-containing lipoproteins are found to be safe and effective in ongoing and future CVOTs, and if their cost is not prohibitive, these agents could provide an entirely new strategy to decrease the worldwide burden of cardiometabolic diseases.

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