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Wołowiec, �.;  Osiak, J.;  Wołowiec, A.;  Wijata, A.;  Grześk, E.;  Kozakiewicz, M.;  Banach, J.;  Nowaczyk, A.;  Nowaczyk, J.;  Grześk, G. Small Interfering RNA in Inhibition of PCSK-9. Encyclopedia. Available online: https://encyclopedia.pub/entry/40732 (accessed on 16 November 2024).
Wołowiec �,  Osiak J,  Wołowiec A,  Wijata A,  Grześk E,  Kozakiewicz M, et al. Small Interfering RNA in Inhibition of PCSK-9. Encyclopedia. Available at: https://encyclopedia.pub/entry/40732. Accessed November 16, 2024.
Wołowiec, Łukasz, Joanna Osiak, Anna Wołowiec, Aleksandra Wijata, Elżbieta Grześk, Mariusz Kozakiewicz, Joanna Banach, Alicja Nowaczyk, Jacek Nowaczyk, Grzegorz Grześk. "Small Interfering RNA in Inhibition of PCSK-9" Encyclopedia, https://encyclopedia.pub/entry/40732 (accessed November 16, 2024).
Wołowiec, �.,  Osiak, J.,  Wołowiec, A.,  Wijata, A.,  Grześk, E.,  Kozakiewicz, M.,  Banach, J.,  Nowaczyk, A.,  Nowaczyk, J., & Grześk, G. (2023, February 01). Small Interfering RNA in Inhibition of PCSK-9. In Encyclopedia. https://encyclopedia.pub/entry/40732
Wołowiec, Łukasz, et al. "Small Interfering RNA in Inhibition of PCSK-9." Encyclopedia. Web. 01 February, 2023.
Small Interfering RNA in Inhibition of PCSK-9
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This entry is adapted from the peer-reviewed paper 10.3390/pharmaceutics15020323

Dyslipidemia is listed among important cardiovascular disease risk factors. Treating lipid disorders is difficult, and achieving desirable levels of LDL-cholesterol (LDL-C) is essential in both the secondary and primary prevention of cardiovascular disease. Statins became the basis of lipid-lowering therapy. Nevertheless, these drugs are often insufficient due to their side effects and restrictive criteria for achieving the recommended LDL-C values. Even the addition of other drugs, i.e., ezetimibe, does not help one achieve the target LDL-C. The discovery of proprotein convertase subtilisin/kexin type 9 (PCSK9) discovery has triggered intensive research on a new class of protein-based drugs. The protein PCSK9 is located mainly in hepatocytes and is involved in the metabolism of LDL-C. In the beginning, antibodies against the PCSK9 protein, such as evolocumab, were invented. The next step was inclisiran. Inclisiran is a small interfering RNA (siRNA) that inhibits the expression of PCSK9 by binding specifically to the mRNA precursor of PCSK9 protein and causing its degradation.

inclisiran PCSK9 siRNA dyslipidemia

1. Introduction

Dyslipidemia, especially elevated levels of LDL cholesterol (LDL-C), is mentioned as a substantial risk factor for cardiovascular disease. A high concentration of LDL-C is regarded as a great risk of atherosclerosis, including coronary artery disease. The main causal and modifiable atherosclerotic cardiovascular disease (ASCVD) risk factors are blood apolipoprotein-B-containing lipoproteins (especially LDL-C), high blood pressure, cigarette smoking, and diabetes mellitus (DM). Modern cardiovascular pharmacotherapy, especially for diseases of atherosclerotic etiology, is extremely multidirectional [1][2]. Among them, the most important is the intervention at the level of the vascular endothelium [3][4], modifying the release and production of mediators and, secondarily, the functions of the receptor systems of signal conducting systems [3][5]. Another direction of influence is the influence on the function of blood platelets responsible for the progression of the disease and its exacerbations [6][7][8], as well as the growth of atherosclerotic plaques [9][10]. Cardiovascular diseases (CVD) are responsible for over 4 million deaths annually in Europe [11]. The number of people diagnosed with primary hypercholesterolemia and mixed dyslipidemia has doubled in recent years [12]. Statins have invariably been the first-line drugs in the treatment of lipid disorders for many years. Besides, ezetimibe (ATC code: C10AX09 [13]) is also widely used. Despite intensive lipid-lowering therapy with a high-dose statin and ezetimibe, many patients still do not achieve the recommended LDL-C levels, often due to side effects [14]. The new target is the PCSK9 (proprotein convertase subtilisin/kexin 9) protein [15]. PCSK9 is a protein located mainly in hepatocytes and plays a role in the metabolism of LDL-C. The discovery of the PCSK9 protein has led to the creation of a new group of drugs—PCSK9 inhibitors, which include two monoclonal antibodies—evolocumab (ATC code: C10AX13 [16]) and alirocumab (ATC code: C10AX14 [17]). The combination of a PCSK9 inhibitor, high-intensity statin treatment, and ezetimibe reduces LDL-C by approximately 85% [18]. An even newer alternative approach to PCSK9 relies on RNA interference. Inclisiran (ATC code: C10AX16 [19]), a low molecular weight compound, interferes with RNA (siRNA), inhibiting PCSK9 expression. The mechanism of this process involves specifically binding to the mRNA precursor of PCSK9 protein and its further degradation [20]. Unlike monoclonal antibodies, which only lower the extracellular levels of PCSK9, inclisiran lowers the intra- and extracellular levels of PCSK9 [21]. It has been shown to decrease LDL-C levels up to approximately 50% depending on the dose [22]. So far, it has been noticed that inhibitors of PCSK9 do not increase the risk of diabetes or muscle pain and myopathy—as is the case with statin therapy [23].

2. Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9)

PCSK9 (initially named neural apoptosis-regulated convertase-1) is a key protein regulating the level of circulating low-density lipoprotein cholesterol (LDL-C) [24]. The work published in 2003, which gave rise to research on the PCSK9 protein, was a discovery made in French families—in people without mutations in the LDLR or apolipoprotein B gene but with very high levels of LDL-C [25]. This protein is most highly expressed in hepatocytes. In addition to hepatocytes, the expression of PCSK9 was noted in the cells of the small intestine, and its much smaller amounts were also noted in the thymus, lungs, kidneys, and spleen [26].
LDL-C is cleared from the circulation by the LDL receptor (LDLR). The pro-protein convertase subtilisin/kexin 9 (PCSK9) enhances the degradation of LDLRs in endosomes/lysosomes, resulting in an increase in circulating LDL-C [27]. Indeed, PCSK9 is a serine protease belonging to the proprotein convertase family, and essential for the metabolism of LDL particles by inhibiting LDLR recirculation to the cell surface with the consequent upregulation of LDLR-dependent LDL-C levels [28]. Some studies also suggest a role for PCSK9 in increasing tumor metastasis [29][30]. As it turns out, the role of PCSK9 goes beyond the regulation of circulating lipid levels, and its inhibition may have positive pleiotropic effects in patients at increased cardiovascular disease risk [31]. One study also showed that PCSK9 levels are associated with the progression of atherosclerosis, as reflected by the total area of atherosclerotic plaques, regardless of plasma LDL-C concentration [32].

3. Anti-PCSK9 Antibodies

Research on the PCSK9 protein contributed to the development of antibodies against the PCSK9 protein—evolocumab, alirocumab, and bococizumab. Unlike evolocumab and alirocumab, which are monoclonal antibodies, bococizumab is a humanized antibody (containing a few percent of mouse proteins). It was evaluated in the SPIRE-1 and SPIRE-2 studies; it caused a noticeable decrease in the hypolipemic effect after several months related to the formation of antibodies against the drug molecule, but a frequent occurrence of allergic reactions at the injection site was also observed, and for this reason, the study was suspended [33]. Currently, the FDA and EMA have approved evolocumab and alirocumab. They are antibodies against PCSK9 and drugs with a low potential for side effects. The main adverse events were injection site pain, back pain, nasopharyngitis, headache, upper respiratory tract infection, and flu-like symptoms (7.5%) [23]. PCSK9 inhibitors do not have an adverse effect on glucose metabolism and the increase in the number of new cases of diabetes. This has been demonstrated in the FOURIER (evolocumab), OSLER-1 (evolocumab), and ODDYSEY LONG (alirocumab) studies, among others [34][35][36][37]. The blockade of PCSK9 by evolocumab significantly reduced cardiovascular risk in diabetic and non-diabetic patients. One of the major limitations of statin therapy is muscle pain and the risk of myopathy. The DESCARTES study (Durable Effect of PCSK9 Antibody Compared with Placebo Study) showed that side effects (an increase in creatine kinase above normal level and muscle pain) were observed at the same level in both groups (placebo vs. evolocumab) [38]. It can also be concluded that previous studies have not shown that therapy with a PCSK9 inhibitor has a harmful effect on cognitive functions [39][40].

4. Small Interfering RNA—Short History and Mechanism

Eukaryotic mRNAs are molecules that live longer than those found in bacteria (for mammals this time is several hours). Due to the differences in half-life, scientists wondered what the processes responsible for mRNA degradation were and how they were controlled. In 1998, Fire et al. discovered the mechanism of RNA interference, which revolutionized the understanding of gene regulation. They established that double-stranded RNA molecules are the silencing effectors in Caenorhabditis elegans [41]. In their experiment, they used single-stranded RNA (ssRNA) or double-stranded RNA (dsRNA) to disrupt muscle function. The results they obtained indicate that the occurrence of an effective knockdown led to phenotypic muscle twitching of Caenorhabditis elegans. Moreover, the only way to increase the efficiency of ssRNA was to simultaneously inject ssRNA with the antisense strand, which suggests that hybridization of ssRNA to dsRNA is a precondition for gene silencing [42].
The target RNA silencing molecule must be double-stranded, which excludes cellular mRNAs but includes viral genomes, many of which are double-stranded RNAs in their native state, or double-stranded RNAs are intermediate in their replication. Double-stranded RNA is recognized by binding proteins, which create a binding site for a ribonuclease called Dicer that cuts the molecule into short interfering RNA (siRNA) 21–28 nucleotides long [43]. Thanks to this, the viral genome is inactivated. However, a question arises: what happens if the viral genes have already been transcribed? It might seem that silencing RNA will not protect the cell from damage. Therefore, the breakthrough discovery was the demonstration of the existence of a second step in the interference process directed at viral mRNA. The siRNA molecules produced by cleavage are target sites for the formation of the RISC complex (RNA-induced silencing complex) [44]. They are separated into single strands; one strand is degraded, and the other strand of each siRNA base pairs with viral mRNAs present in the cell. RISC complex contains an RNA binding protein of the Argonaut family and a cutting and therefore silencing mRNA nuclease [45][46].
Since research on C. elegans, it has been shown that RNA interference occurs in all eukaryotes with single exceptions, for example, in S. cerevisiae. The interference process itself has been associated with phenomena including RNA degradation. For example, the movement of some types of mobile elements is mediated by double-stranded RNA molecules. This is one way for eukaryotic organisms to prevent the mass multiplication of transposons in their genomes.
RNAi therapies represent a huge opportunity in the treatment of many diseases. siRNA has the ability to target and silence virtually any gene of interest. Consequently, siRNA can be a powerful tool for biomedical research and drug discovery [47]. Therefore, during the development of low molecular weight inhibitors targeting protein-resistant oncogenes, examples such as RAS and MYC posed a serious challenge [48][49]. siRNA-based therapy can turn the tide of many debilitating diseases, as siRNAs are easily engineered, and strong siRNA identification can be done in weeks compared to years for drug development [50]. Another advantage is that strong siRNA sequences are usually active at extremely low (picomolar) concentrations, and they can be designed for any gene of interest with the appropriate tools [50][51].

5. siRNA Drugs

Research conducted for nearly 20 years on siRNA finally contributed to the approval by the FDA in November 2018 of the first drug of the siRNA group—patisiran (ATC code: N07XX12 [19]). It was a groundbreaking event that opened the door for new drugs to be introduced to the market. Patisiran is a drug used in the polyneuropathy of hereditary TTR-dependent amyloidosis (hATTR) [52][53]. In a 12-month analysis of the ongoing study-OLE study, conducted in 211 patients, patisiran appeared to maintain efficacy with an acceptable safety profile in patients with hereditary TTR-dependent amyloidosis with polyneuropathy [54]. In one of the studies, it was additionally shown that patisiran can stop or reverse the progression of cardiac symptoms of hATTR amyloidosis [55]. The most common treatment-related adverse event was mild or moderate infusion-related reactions [54].
Another drug was givosiran (ATC code: A16AX16 [19]). Givosiran is a drug approved for the treatment of patients with acute porphyria (AHP) [56]. Among patients with acute intermittent porphyria, those who received givosiran had a significantly lower rate of porphyria attacks and better scores on many other symptoms of the disease than those who received a placebo [57][58]. Adverse effects on the liver (increased levels of aminotransferases) and kidneys (changes in creatinine levels) have been recorded as side effects, among others [57].
Lumasiran (ATC code: A16AX18 [59]) was the third consecutive small interfering ribonucleic acid approved by the EMA and FDA. It is indicated for the treatment of a rare genetic disease—primary hyperoxaluria type 1. The effectiveness of this drug has been confirmed in the ILLUMINATE-A, ILLUMINATE-B, and ILLUMINATE-C studies [60][61][62]. Next was inclisiran, a drug registered in the treatment of ASCVD (atherosclerotic cardiovascular disease) and HeFH (heterozygous familial hypercholesterolemia)—this drug will be discussed in more detail later in the article. The last drug approved this year by the EMA and FDA was vutrisiran—a drug used in hereditary transthyretin amyloidosis (ATTRv) with polyneuropathy. In studies, vutrisiran significantly improved many disease-relevant outcomes compared to placebo, with an acceptable safety profile [63]. Research is underway to introduce further siRNA drugs—nedosiran, fitusiran, tivanisiran, and olpasiran [64][65][66][67].

6. Pharmacokinetic and Pharmacodynamic Properties

The systemic exposure to inclisiran increased approximately dose-proportionally over the range of 24 mg to 756 mg after a single subcutaneous administration. At a dose of 284 mg, plasma concentrations reached maximum concentrations approximately 4 h post-dose, with a mean Cmax of 509 ng/mL. In vitro, at appropriate clinical plasma concentrations inclisiran is 87% protein bounded. After the subcutaneous administration of a single 284-mg dose, the apparent volume of distribution was ≈500 L [68].
Based on preclinical data, inclisiran has been shown to have high uptake and selectivity for hepatocytes [69]. Inclisiran is mainly metabolized by non-specific nucleases to inactive shorter nucleotides [70]. The drug is almost completely cleared from the circulation within 24 h after subcutaneous injection [71]. The terminal elimination half-life of inclisiran is approximately 9 h and accumulation does not occur with repeated dosing. It is estimated that sixteen percent of inclisiran is cleared by the kidneys [68]. Regardless of renal impairment, inclisiran has a short plasma half-life (5–10 h) [72].
The effects on PCSK9 and LDL cholesterol levels were sustained for at least 180 days after initiation of treatment, with little variability over a period of 6 months after receiving the first dose [73]. Doses of 300 mg or more (in single or multiple doses) significantly lowered PCSK9 and LDL-C levels for at least 6 months. There was also a reduction in PCSK9 to 83.8% and LDL cholesterol to 59.7% at a dose of 300 mg [73]. The subcutaneous administration of inclisiran provided tissue-specific delivery and efficacy, leading to the potent and dose-dependent inhibition of PCSK9 gene expression. The study shows that 1 mg/kg was an approximate effective dose, causing 50% inhibition. For comparison, 6 mg/kg was an approximate effective dose, causing 80% inhibition of PCSK9, and then, the maximum inhibitions of PCSK9 and LDL-C were 85% and 68% [74]. Moreover, the study showed that the inclisiran-treated patients had lower non-HDL cholesterol, lipoprotein(a), and apolipoprotein B levels. They also had higher levels of HDL cholesterol [75].
In patients with moderate hepatic impairment, the pharmacokinetic exposure of inclisiran was up to two-fold higher compared to patients with normal hepatic function, while the pharmacodynamic effect was relatively unchanged. Studies have shown that inclisiran is generally safe and well tolerated in patients with mild or moderate hepatic impairment, without the need for dose adjustment. The pharmacodynamic effects and safety profile of inclisiran were similar in subjects with normal and impaired renal function. There is no need to adjust the inclisiran dose in these patients [76].
Therefore, inclisiran can probably be used safely even in patients with advanced kidney disease (CrCl level, 15–29 mL/min). However, it should be noted that people with acute kidney disease, those who had undergone kidney transplantation, and those requiring hemodialysis were excluded from the study—further studies are certainly needed in these groups of patients [77].

7. Safety and Side-Effect Profile

All adverse events were mild to moderate in severity and, importantly, did not cause discontinuation of the study in any of the participants. The most commonly reported adverse events are cough, musculoskeletal pain, headache, back pain, diarrhea, and nasopharyngitis [78][79]. One study participant taking a statin showed an asymptomatic increase in GGTP and ALT, with no increase in bilirubin—the increase in enzymes subsided after stopping the statins. In addition, a few study participants developed a delayed, mild, self-limited injection site rash as well as mild, reversible discoloration from the injection site rash. No changes in the corrected QT interval (QTc) were observed [73]. Based on contemporary scientific reports, one can conclude that inclisiran is a well-tolerated LDL-C-decreasing agent. However, as with any new substance, the potential off-target effects and the long-term safety of the drug should be closely monitored. A study that assesses long-term tolerance to inclisiran administration is the ORION-3 study (extension study of the phase 2 ORION-1 trial). The long-awaited results were published a few days ago in Lancet. The above-mentioned study outcomes showed that twice-yearly inclisiran provided sustained reductions in LDL-C and PCSK9 levels and was well tolerated for 4 years [80]. Patients receiving inclisiran in ORION-1 received inclisiran during ORION-3 as well, whereas patients receiving placebo in ORION-1 received evolocumab for up to 1 year and then transitioned to inclisiran for the remainder of the study. The treatment-emergent adverse events, which were possibly related to the study’s medication, occurred in 79 (28%) of 284 patients (in the inclisiran-only arm)—the most common were injection site reaction (16 patients [5.6%]), injection site erythema and injection site pain (12 patients [4.2%]). A hepatic enzyme increase occurred in 4 patients (1,4%), as well as muscle spasms. Treatment-emergent serious adverse events, possibly related to the study drug (as reported by the investigator), occurred in 4 patients and included sinus tachycardia, acute cholecystitis (in a patient known with gallstones), hepatic fibrosis (in a patient with fatty liver disease) and hepatic enzyme increased (in a patient with chronic hepatitis C and high alcohol intake) [80]. In the ORION-3 study, each reported side effect was summarized in detail in the supplementary material to Lancet’s article. Another study examining the efficacy, safety, and tolerability of long-term dosing of inclisiran is the ORION-8 study. The study will include more than 3000 participants previously involved in the ORION-3, ORION9, ORION 10, and ORION-11 studies. The estimated data collection completion time is the end of 2023 [81]. As rightly noted, inclisiran could be a very interesting option in pregnancy, as it can be used just before and immediately after pregnancy for about 9 months between injections [82]. However, as a precaution—due to a lack of adequate research, it is recommended to avoid using inclisiran during pregnancy.

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Subjects: Cardiac & Cardiovascular Systems
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Łukasz Wołowiec
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Joanna Osiak
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Anna Wołowiec
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Aleksandra Wijata
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Elżbieta Grześk
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Mariusz Kozakiewicz
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Joanna Banach
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Alicja Nowaczyk
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Jacek Nowaczyk
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Grzegorz Grześk
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Update Date: 02 Feb 2023
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