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      Antisense Technology: An Emerging Platform for Cardiovascular Disease Therapeutics

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          Abstract

          Antisense oligonucleotides and small interfering RNAs, which suppress the translation of specific mRNA target proteins, are emerging as important therapeutic modalities for the treatment of cardiovascular disease. Over the last 25 years, the advances in all aspects of antisense technology, as well as a detailed understanding of the mechanism of action of antisense drugs, have enabled their use as therapeutic agents. These advancements culminated in the FDA approval of the first chronically administered cardiovascular antisense therapeutic, mipomersen, which targets hepatic apolipoprotein B mRNA. This review provides a brief history of antisense technology, highlights the progression of mipomersen from preclinical studies to multiple Phase III registration trials, and gives an update on the status of other cardiovascular antisense therapeutics currently in the clinic.

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          Passenger-strand cleavage facilitates assembly of siRNA into Ago2-containing RNAi enzyme complexes.

          Christian Matranga, Yukihide Tomari, Chanseok Shin … (2005)
          In the Drosophila and mammalian RNA interference pathways, siRNAs direct the protein Argonaute2 (Ago2) to cleave corresponding mRNA targets, silencing their expression. Ago2 is the catalytic component of the RNAi enzyme complex, RISC. For each siRNA duplex, only one strand, the guide, is assembled into the active RISC; the other strand, the passenger, is destroyed. An ATP-dependent helicase has been proposed first to separate the two siRNA strands, then the resulting single-stranded guide is thought to bind Ago2. Here, we show that Ago2 instead directly receives the double-stranded siRNA from the RISC assembly machinery. Ago2 then cleaves the siRNA passenger strand, thereby liberating the single-stranded guide. For siRNAs, virtually all RISC is assembled through this cleavage-assisted mechanism. In contrast, passenger-strand cleavage is not important for the incorporation of miRNAs that derive from mismatched duplexes.
          Article 0 comments Cited 313 times – based on 0 reviews     Review now
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            RNAi-mediated gene silencing in non-human primates.

            Tracy Zimmermann, Amy Lee, Akin Akinc … (2006)
            The opportunity to harness the RNA interference (RNAi) pathway to silence disease-causing genes holds great promise for the development of therapeutics directed against targets that are otherwise not addressable with current medicines. Although there are numerous examples of in vivo silencing of target genes after local delivery of small interfering RNAs (siRNAs), there remain only a few reports of RNAi-mediated silencing in response to systemic delivery of siRNA, and there are no reports of systemic efficacy in non-rodent species. Here we show that siRNAs, when delivered systemically in a liposomal formulation, can silence the disease target apolipoprotein B (ApoB) in non-human primates. APOB-specific siRNAs were encapsulated in stable nucleic acid lipid particles (SNALP) and administered by intravenous injection to cynomolgus monkeys at doses of 1 or 2.5 mg kg(-1). A single siRNA injection resulted in dose-dependent silencing of APOB messenger RNA expression in the liver 48 h after administration, with maximal silencing of >90%. This silencing effect occurred as a result of APOB mRNA cleavage at precisely the site predicted for the RNAi mechanism. Significant reductions in ApoB protein, serum cholesterol and low-density lipoprotein levels were observed as early as 24 h after treatment and lasted for 11 days at the highest siRNA dose, thus demonstrating an immediate, potent and lasting biological effect of siRNA treatment. Our findings show clinically relevant RNAi-mediated gene silencing in non-human primates, supporting RNAi therapeutics as a potential new class of drugs.
            Article 0 comments Cited 303 times – based on 0 reviews     Review now
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              Genetic associations with valvular calcification and aortic stenosis.

              George Thanassoulis, Catherine Y Campbell, David S Owens … (2013)
              Limited information is available regarding genetic contributions to valvular calcification, which is an important precursor of clinical valve disease. We determined genomewide associations with the presence of aortic-valve calcification (among 6942 participants) and mitral annular calcification (among 3795 participants), as detected by computed tomographic (CT) scanning; the study population for this analysis included persons of white European ancestry from three cohorts participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (discovery population). Findings were replicated in independent cohorts of persons with either CT-detected valvular calcification or clinical aortic stenosis. One SNP in the lipoprotein(a) (LPA) locus (rs10455872) reached genomewide significance for the presence of aortic-valve calcification (odds ratio per allele, 2.05; P=9.0×10(-10)), a finding that was replicated in additional white European, African-American, and Hispanic-American cohorts (P<0.05 for all comparisons). Genetically determined Lp(a) levels, as predicted by LPA genotype, were also associated with aortic-valve calcification, supporting a causal role for Lp(a). In prospective analyses, LPA genotype was associated with incident aortic stenosis (hazard ratio per allele, 1.68; 95% confidence interval [CI], 1.32 to 2.15) and aortic-valve replacement (hazard ratio, 1.54; 95% CI, 1.05 to 2.27) in a large Swedish cohort; the association with incident aortic stenosis was also replicated in an independent Danish cohort. Two SNPs (rs17659543 and rs13415097) near the proinflammatory gene IL1F9 achieved genomewide significance for mitral annular calcification (P=1.5×10(-8) and P=1.8×10(-8), respectively), but the findings were not replicated consistently. Genetic variation in the LPA locus, mediated by Lp(a) levels, is associated with aortic-valve calcification across multiple ethnic groups and with incident clinical aortic stenosis. (Funded by the National Heart, Lung, and Blood Institute and others.).
              Article 0 comments Cited 260 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Richard G. Lee: +1-760-6032793 , +1-760-6032600 , rlee@isisph.com
                Journal
                Journal ID (nlm-ta): J Cardiovasc Transl Res
                Journal ID (iso-abbrev): J Cardiovasc Transl Res
                Title: Journal of Cardiovascular Translational Research
                Publisher: Springer US (Boston )
                ISSN (Print): 1937-5387
                ISSN (Electronic): 1937-5395
                Publication date (Electronic): 16 July 2013
                Publication date PMC-release: 16 July 2013
                Publication date (Print): 2013
                Volume: 6
                Pages: 969-980
                Affiliations
                Isis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, CA 92010 USA
                Author notes

                Associate Editor Enrique Lara-Pezzi oversaw the review of this article

                Article
                Publisher ID: 9495
                DOI: 10.1007/s12265-013-9495-7
                PMC ID: 3838598
                PubMed ID: 23856914
                SO-VID: 41c2bef2-45b9-4657-9cb9-6f791bf12de0
                Copyright © © The Author(s) 2013
                License:

                Open Access This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.

                History
                Date received : 15 May 2013
                Date accepted : 21 June 2013
                Categories
                Subject: Article
                Custom metadata
                issue-copyright-statement © Springer Science+Business Media New York 2013

                ScienceOpen disciplines: Cardiovascular Medicine
                Keywords: antisense oligonucleotides,atherosclerosis,thrombosis,dyslipidemia,small interfering rnas,coagulation,apolipoprotein b
                Data availability:
                ScienceOpen disciplines: Cardiovascular Medicine
                Keywords: antisense oligonucleotides, atherosclerosis, thrombosis, dyslipidemia, small interfering rnas, coagulation, apolipoprotein b

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