Effectiveness and Safety of Inclisiran, A Novel Long-Acting RNA Therapeutic Inhibitor of Proprotein Convertase Subtilisin/Kexin 9

Ghosh, Gopal Chandra; Bandyopadhyay, Dhrubajyoti; Ghosh, Raktim; Mondal, Samhati; Herzog, Eyal

doi:10.1016/j.amjcard.2018.06.023

Cited by 19 publications

(2 citation statements)

References 21 publications

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“…Inclisiran wirkt ähnlich stark wie die Antikörper, muss aber nur alle 3 bzw. 6 Monate injiziert werden [23]. Eine kardiovaskuläre Endpunktstudie liegt noch nicht vor.…”

Section: Medikamentöse Therapie Mit Statinenunclassified

Hypercholesterinämie – Wen, wann, wie behandeln?

Merkel

2023

Dtsch Med Wochenschr

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Was ist neu? LDL-Cholesterin und Arteriosklerose In den letzten Jahren haben klinisch wissenschaftliche Daten zu LDL-Cholesterin und Arteriosklerose zu immer niedrigeren LDL-Cholesterin-Zielwerten und zur Ausweitung der Indikation für eine medikamentöse Lipidtherapie auf immer größere Bevölkerungs- bzw. Patientengruppen geführt. Kardiovaskuläres Risiko und Therapieziele Bei der Einschätzung des kardiovaskulären Risikos von Patienten werden neben z.B. vorbestehender kardiovaskulärer Erkrankung, familiärer Hypercholesterinämie und Typ-II-Diabetes auch Typ-I-Diabetes, diabetische Folgeerkrankungen, Niereninsuffizienz und subklinische Arteriosklerose berücksichtigt. Lipidologische Therapie zur kardiovaskulären Risikoreduktion Zur Berechnung des kardiovaskulären Risikos in der Primärprävention wurden die Kalkulatoren SCORE2 und SCORE-OP neu entwickelt. Eine diätetische Intervention gehört an den Anfang jeder lipidsenkenden Therapie. Bempedoinsäure und Inclisiran stellen neue medikamentöse Therapieoptionen dar. Therapeutisches Vorgehen Nach der Anamnese erfolgt die Zielwertsetzung und die stufenweise Aufdosierung eines Statins. Nach 6–12 Wochen wird diese Therapie ggf. mit einem ACL-Inhibitor kombiniert, um die Wirkung zu verstärken.

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“…Inclisiran wirkt ähnlich stark wie die Antikörper, muss aber nur alle 3 bzw. 6 Monate injiziert werden [23]. Eine kardiovaskuläre Endpunktstudie liegt noch nicht vor.…”

Section: Medikamentöse Therapie Mit Statinenunclassified

Hypercholesterinämie – Wen, wann, wie behandeln?

Merkel

2023

Dtsch Med Wochenschr

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“…Peptide-based vaccines may prolong the window of efficacy; , however, targeting a human protein through anti-self-antibodies carries inherent safety risks . Other promising approaches to block PCSK9 activity include CRISPR-Cas9 genome editing and siRNA-based therapies. − …”

Section: Introductionmentioning

confidence: 99%

Regulation of Lipoprotein Homeostasis by Self-Assembling Peptides

Harbour

Casillas

Siddiqui

et al. 2020

ACS Appl. Bio Mater.

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High levels of serum low-density lipoprotein (LDL) cholesterol contribute to atherosclerosis, a key risk factor of cardiovascular diseases. PCSK9 is a circulatory enzyme that downregulates expression of hepatic LDL receptors, concomitantly increasing serum LDL-C. This work investigates a small, self-assembling peptide, EPep2-8, as a peptide inhibitor of PCSK9. EPep2-8 is a multidomain peptide comprising a self-assembling domain, E2, conjugated to a bioactive domain, Pep2-8, previously shown to inhibit PCSK9. The E2 domain facilitates self-assembly of EPep2-8 into long, nanofibrous polymers with an underlying supramolecular β-sheet secondary structure. Intermolecular interactions between nanofibers drive EPep2-8 to form a thixotropic and cytocompatible hydrogel in aqueous and charge-neutral solutions. These properties enable EPep2-8 to be delivered as an in situ depot for regulation of lipoprotein homeostasis. In surface plasmon resonance studies, EPep2-8 bound specifically to PCSK9 with an apparent, noncovalent, and irreversible dissociation, significantly improving the binding affinity of Pep2-8 alone (K D = 667 ± 48 nM). Increased binding affinity of EPep2-8 is primarily due to the superstoichiometric interaction of the peptide with PCSK9. Promisingly, EPep2-8 retains bioactivity in vitro, engendering dose-dependent uptake of LDL-C in hepatocytes. This mechanism of self-assembly on a target site may be a simple method to improve the affinity of peptide inhibitors.

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Opportunities and challenges for antisense oligonucleotide therapies

Kuijper

Bergsma

Pijnappel

et al. 2020

J of Inher Metab Disea

109

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Antisense oligonucleotide (AON) therapies involve short strands of modified nucleotides that target RNA in a sequence‐specific manner, inducing targeted protein knockdown or restoration. Currently, 10 AON therapies have been approved in the United States and Europe. Nucleotides are chemically modified to protect AONs from degradation, enhance bioavailability and increase RNA affinity. Whereas single stranded AONs can efficiently be delivered systemically, delivery of double stranded AONs requires capsulation in lipid nanoparticles or binding to a conjugate as the uptake enhancing backbone is hidden in this conformation. With improved chemistry, delivery vehicles and conjugates, doses can be lowered, thereby reducing the risk and occurrence of side effects. AONs can be used to knockdown or restore levels of protein. Knockdown can be achieved by single stranded or double stranded AONs binding the RNA transcript and activating RNaseH‐mediated and RISC‐mediated degradation respectively. Transcript binding by AONs can also prevent translation, hence reducing protein levels. For protein restoration, single stranded AONs are used to modulate pre‐mRNA splicing and either include or skip an exon to restore protein production. Intervening at a genetic level, AONs provide therapeutic options for inherited metabolic diseases as well. This review provides an overview of the different AON approaches, with a focus on AONs developed for inborn errors of metabolism.

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Effectiveness and Safety of Inclisiran, A Novel Long-Acting RNA Therapeutic Inhibitor of Proprotein Convertase Subtilisin/Kexin 9

Cited by 19 publications

References 21 publications

Hypercholesterinämie – Wen, wann, wie behandeln?

Hypercholesterinämie – Wen, wann, wie behandeln?

Regulation of Lipoprotein Homeostasis by Self-Assembling Peptides

Opportunities and challenges for antisense oligonucleotide therapies

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