RNA therapeutics inactivate PCSK9 by inducing a unique intracellular retention form

Journal of Molecular and Cellular Cardiology
Cristina S J RochaC I Edvard Smith

Abstract

Hypercholesterolemia is a medical condition often characterized by high levels of low-density lipoprotein cholesterol (LDL-C) in the blood. Despite the available therapies, not all patients show sufficient responses, especially those with very high levels of LDL-C or those with familial hypercholesterolemia. Regulation of plasma cholesterol levels is very complex and several proteins are involved (both receptors and enzymes). From these, the proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as a promising pharmacologic target. The objective of this work is to develop a new approach to inactivate PCSK9 by splice-switching oligonucleotides (SSOs), converting the normal splice form to a natural, less abundant and inactive, splice variant. For this purpose, a new RNA therapeutic approach for hypercholesterolemia based on SSOs was developed for modulation of the splice pattern of human PCSK9 pre-mRNA. Our results show an increase of the selected splice form at both the mRNA and protein level when compared to non-treated Huh7 and HepG2 cell lines, with concomitant increase of the protein level of the low-density lipoprotein receptor (LDLR) demonstrating the specificity and efficiency of the system. In vivo, full conve...Continue Reading

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Citations

Sep 4, 2015·Expert Opinion on Biological Therapy·Annukka M KiveläSeppo Ylä-Herttuala
Jul 15, 2015·Human Gene Therapy·Karin E LundinC I Edvard Smith
Oct 5, 2018·Annual Review of Pharmacology and Toxicology·C I Edvard Smith, Rula Zain
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Apr 26, 2017·Basic Research in Cardiology·Simon GlerupKlaus-Dieter Schlüter
Nov 13, 2020·Journal of Bioscience and Bioengineering·Takehiro AndoTakashi Kawakami

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