Could siRNA therapeutics change the way we treat dyslipidemia?

KEYWORDS:

• siRNA
• lipids
• cholesterol
• hyperlipidemia

1. Introduction

Cardiovascular disease (CVD) is a leading cause of morbidity and mortality worldwide, and dyslipidemias contribute substantially to CVD risk. Atherosclerotic plaques in the walls of blood vessels are responsible for myocardial infarctions and stroke and are caused by the deposition of cholesterol-carrying, low-density lipoprotein (LDL) particles. Studies and trials have repeatedly demonstrated, across the whole spectrum of cardiovascular risk, that reduction of LDL-cholesterol by 1 µmol/l results in a reduction of about one-quarter in CVD risk [1]. However, it can be challenging to exploit this benefit in clinical practice fully. Statins and other small-molecule oral therapeutics have to be taken daily to maintain concentrations of the drug within the therapeutic range. This can result in challenges in compliance – when any disadvantages of treatment are immediately apparent to the patient, whereas the benefit of reduced risk of future cardiovascular events is far less tangible. Furthermore, a small proportion (<10%) of patients are intolerant to statin therapy [2] and some adults struggle to swallow oral dosage forms [3], limiting the extent to which long-term exposure to LDL-C, and therefore cardiovascular risk, can be reduced.

Statins reduce the endogenous production of cholesterol in the liver, resulting in the upregulation of LDL receptors on hepatocytes and increased hepatic uptake of LDL from the circulation. In the early 2000s, Boileau and colleagues identified PCSK9 as a negative regulator of LDL-receptors and recognized the potential of PCSK9 inhibition to promote the hepatic uptake of LDL from the circulation [4]. PCSK9 is not readily amenable to small-molecule targets, and the first drugs to target these molecules were monoclonal antibodies [5]. However, these agents still require injection every 2–4 weeks, which may present a barrier to adherence.

2. How are siRNA therapeutics used at present?

The central dogma of molecular biology, ‘DNA makes RNA makes proteins,’ led to the recognition that protein expression can be modulated through RNA interference, which has been exploited with increasing sophistication since the 1990s [6]. RNA interference can be achieved using an siRNA molecule, that inhibits the expression of PCSK9 by binding to the host mRNA strand encoding for the protein, causing it to cleave and degrade. In the field of lipid modification, RNA interference (via siRNA) is particularly attractive, because it results in long-lasting changes in protein expression – heralding the possibility of infrequent injections of siRNA agents replacing daily dosing of small molecules [7], potentially avoiding the ‘off target’ adverse effects associated with small molecules and improving adherence and long-term control of plasma lipids. Furthermore, siRNA can be used to reduce the functionality of a wider range of biological molecules than small molecules, which are most effective at inhibiting enzymes and acting on ligands at extracellular receptors.

Indeed, an siRNA agent (inclisiran) against a novel target (proprotein convertase subtilisin/kexin type 9 (PCSK9)) which can be preferentially targeted to the liver using GalNAc-bound nanoparticles [7] has already been exploited in the clinic in the treatment of dyslipidemias and atherosclerosis [8].

Inclisiran has been extensively evaluated in the Orion series of clinical trials. Twice-yearly administration of inclisiran resulted in reductions in LDL cholesterol by 44%, which was sustained over 4 years, and the drug was well tolerated, with injection-site reactions being the most commonly reported adverse effects [9]. Importantly, in a high-risk population, inclisiran significantly reduced major adverse cardiovascular events (MACE) (OR 0.74, 95% CI 0.58–0.94) in a pooled analysis of randomized controlled trials [10].

3. What does the future hold?

Given this successful proof-of concept with inclisiran, how might siRNA therapeutics change the way we treat dyslipidemia? And what are the challenges?

Firstly, RNA-silencing approaches might be exploited in addressing a wider range of cardiovascular-related risk factors. Approaches in development include targeting ANGPTL3 and Apolipoprotein CIII, resulting in reduced serum triglycerides and targeting Apolipoprotein B (an essential component of atherogenic lipoproteins, including LDL). However, in these examples, RNA silencing has been achieved using antisense oligonucleotides rather than siRNA [7]. There, whilst gene silencing has proven effective in the management of dyslipidemias, the optimal technology used to achieve this is not yet clear. Recent advances in CRISPR [11] and base-editing [12] technologies herald the possibility of lifelong treatment of dyslipidemias, with a single course of treatment. Rather, like the MiniDisc/MP3 era, we may have to wait to discover which of several approaches prove optimal in terms of patient acceptability, cost, and clinical effectiveness. It is important to recognize that siRNA and other biological therapies are being developed across the whole spectrum of therapeutics. Inevitably, high incidences of multimorbidity in populations will result in ‘biological polypharmacy’ with patients receiving multiple agents for various diseases and conditions. Careful monitoring and pharmacovigilance will be required to ensure the long-term safety of such approaches, which are not readily amenable to investigation in clinical trials.

It is also important not to call time prematurely on the small-molecule era. Personalized approaches to therapy with existing agents [13,14] and the introduction of new small-molecule agents, such as bempedoic acid [15,16], potentially allow for a lower-cost, effective approach to the management of dyslipidemias, which may be effective for the majority of the population. However, the precise cost of individual medicines will depend upon patent status (older drugs such as statins are clearly cheaper), manufacturing costs (tablets are cheaper to make and administer than biologics), and any localized deals and agreements between healthcare providers and the pharmaceutical industry. When considering cost-effectiveness, the long-term evidence base of statins for efficacy and safety necessarily exceeds that of newer agents.

Nevertheless, siRNAs (and other gene silencing approaches) have a bright future in the management of dyslipidemias, particularly in high-risk patients [17], statin intolerance [2], and those with familial hypercholesterolemia [18], where adequate control of lipids is not achievable with current therapies.

Declarations of interest

PE Penson owns four shares in AstraZeneca PLC and has received honoraria and/or travel reimbursement for events sponsored by AKCEA, Amgen, AMRYT, Link Medical, Mylan, Napp, and Sanofi. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.