Small Interfering RNA to Reduce Lipoprotein(a) in Cardiovascular Disease

O’Donoghue, Michelle L.; Rosenson, Robert S.; Gencer, Baris; López, J. Antonio G.; Lepor, Norman E.; Baum, Seth; Stout, Elmer; Gaudet, Daniel; Knüsel, Beat; Kuder, Julia; Ran, Xinhui; Murphy, Sabina A.; Wang, Huei; Wu, Yanyu; Kassahun, Helina; Sabatine, Marc S.

doi:10.1056/nejmoa2211023

Cited by 235 publications

(131 citation statements)

References 23 publications

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“…In comparison, a single administration of monoclonal antibodies against PCSK9 (evolocumab) resulted in a 14% decrease in Lp(a) [ 112 ]. In a phase 2 study conducted on 281 patients, it was shown that olpasiran therapy significantly reduced the concentration of lipoprotein(a) in patients with diagnosed atherosclerotic cardiovascular disease [ 113 ]. Phase 3 trials are planned, with the primary objective of comparing the effect of olpasiran treatment with a placebo on the risk of death from ischemic heart disease, myocardial infarction, or urgent coronary revascularization in participants with atherosclerotic cardiovascular disease (ASCVD) and elevated Lp(a); however, the recruitment of study participants has not yet started, and the estimated date of completion of the study is December 2026 ( Identifier: NCT05581303) [ 114 ].…”

Section: Olpasiranmentioning

confidence: 99%

Inclisiran—Safety and Effectiveness of Small Interfering RNA in Inhibition of PCSK-9

et al. 2023

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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. For many years, 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. It has been noticed in recent years that siRNA is a powerful tool for biomedical research and drug discovery. The purpose of this work is to summarize the molecular mechanisms, pharmacokinetics, pharmacodynamics of inclisiran and to review the latest research.

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Section: Olpasiranmentioning

confidence: 99%

Inclisiran—Safety and Effectiveness of Small Interfering RNA in Inhibition of PCSK-9

et al. 2023

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“…Eventually, newer emerging therapies targeting specifically apo(a) via ASOs (Pelacarsen) and siRNAs (Olpasiran) are being investigated in phase II and III trials, with encouraging preliminary results in terms of safety and efficacy in reducing plasma Lp(a) levels, and data on the clinical outcome are expected in the coming years [ 76 , 77 , 78 ].…”

Section: Lipoprotein(a)mentioning

confidence: 99%

Secondary Cardiovascular Prevention after Acute Coronary Syndrome: Emerging Risk Factors and Novel Therapeutic Targets

Silverio

Cancro

Esposito

et al. 2023

JCM

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The control of cardiovascular risk factors, the promotion of a healthy lifestyle, and antithrombotic therapy are the cornerstones of secondary prevention after acute coronary syndrome (ACS). However, many patients have recurrent ischemic events despite the optimal control of traditional modifiable risk factors and the use of tailored pharmacological therapy, including new-generation antiplatelet and lipid-lowering agents. This evidence emphasizes the importance of identifying novel risk factors and targets to optimize secondary preventive strategies. Lipoprotein(a) (Lp(a)) has emerged as an independent predictor of adverse events after ACS. New molecules such as anti-PCSK9 monoclonal antibodies, small interfering RNAs, and antisense oligonucleotides can reduce plasma Lp(a) levels and are associated with a long-term outcome benefit after the index event. The inflammatory stimulus and the inflammasome, pivotal elements in the development and progression of atherosclerosis, have been widely investigated in patients with coronary artery disease. More recently, randomized clinical trials including post-ACS patients treated with colchicine and monoclonal antibodies targeting cytokines yielded promising results in the reduction in major cardiovascular events after an ACS. Gut dysbiosis has also raised great interest for its potential pathophysiological role in cardiovascular disease. This evidence, albeit preliminary and needing confirmation by larger population-based studies, suggests the possibility of targeting the gut microbiome in particularly high-risk populations. The risk of recurrent ischemic events after ACS is related to the complex interaction between intrinsic predisposing factors and environmental triggers. The identification of novel risk factors and targets is fundamental to customizing patient clinical management with a precision medicine perspective.

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“…The OCEAN [a]-DOSE trial tested Olpasiran, an siRNA targeting Lp (a). This multicenter, randomized, double-blind, placebo-controlled trial took place at 34 sites in seven countries [ 99 ]. 281 patients were randomized in a 1:1:1:1:1 ratio to varying doses of olpasiran (10 mg every 12 weeks, 75 mg every 12 weeks, 225 mg every 12 weeks, or 225 mg every 24 weeks) or placebo, administered subcutaneously.…”

Section: Gene Silencing: Short Interfering Rna (Sirna)mentioning

confidence: 99%

Monoclonal Antibodies, Gene Silencing and Gene Editing (CRISPR) Therapies for the Treatment of Hyperlipidemia—The Future Is Here

et al. 2023

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Hyperlipidemia is a significant risk factor for atherosclerotic cardiovascular disease. Undertreatment of elevated lipids persists despite existing therapies. Here, we provide an update on monoclonal antibodies, gene silencing therapies, and gene editing techniques for the management of hyperlipidemia. The current era of cutting-edge pharmaceuticals targeting low density lipoprotein cholesterol, PCSK9, lipoprotein (a), angiopoietin-like 3, and apolipoprotein C3 are reviewed. We outline what is known, studies in progress, and futuristic goals. This review of available and upcoming biotechnological lipid therapies is presented for clinicians managing patients with familial hyperlipidemia, statin intolerance, hypertriglyceridemia, or elevated lipoprotein (a) levels.

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Small Interfering RNA to Reduce Lipoprotein(a) in Cardiovascular Disease

Cited by 235 publications

References 23 publications

Inclisiran—Safety and Effectiveness of Small Interfering RNA in Inhibition of PCSK-9

Inclisiran—Safety and Effectiveness of Small Interfering RNA in Inhibition of PCSK-9

Secondary Cardiovascular Prevention after Acute Coronary Syndrome: Emerging Risk Factors and Novel Therapeutic Targets

Monoclonal Antibodies, Gene Silencing and Gene Editing (CRISPR) Therapies for the Treatment of Hyperlipidemia—The Future Is Here

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