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      Mechanisms and strategies for effective delivery of antisense and siRNA oligonucleotides

      research-article
      Author(s): * , , ,
      Publication date (Electronic):
      Journal: Nucleic Acids Research
      Publisher: Oxford University Press

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          Abstract

          The potential use of antisense and siRNA oligonucleotides as therapeutic agents has elicited a great deal of interest. However, a major issue for oligonucleotide-based therapeutics involves effective intracellular delivery of the active molecules. In this Survey and Summary, we review recent reports on delivery strategies, including conjugates of oligonucleotides with various ligands, as well as use of nanocarrier approaches. These are discussed in the context of intracellular trafficking pathways and issues regarding in vivo biodistribution of molecules and nanoparticles. Molecular-sized chemical conjugates and supramolecular nanocarriers each display advantages and disadvantages in terms of effective and nontoxic delivery. Thus, choice of an optimal delivery modality will likely depend on the therapeutic context.

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          Control of translation and mRNA degradation by miRNAs and siRNAs.

          Marco Valencia-Sanchez, Jidong Liu, Gregory Hannon … (2006)
          The control of translation and mRNA degradation is an important part of the regulation of gene expression. It is now clear that small RNA molecules are common and effective modulators of gene expression in many eukaryotic cells. These small RNAs that control gene expression can be either endogenous or exogenous micro RNAs (miRNAs) and short interfering RNAs (siRNAs) and can affect mRNA degradation and translation, as well as chromatin structure, thereby having impacts on transcription rates. In this review, we discuss possible mechanisms by which miRNAs control translation and mRNA degradation. An emerging theme is that miRNAs, and siRNAs to some extent, target mRNAs to the general eukaryotic machinery for mRNA degradation and translation control.
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            The multiple faces of caveolae.

            Robert Parton, Kai Simons (2007)
            Caveolae are a highly abundant but enigmatic feature of mammalian cells. They form remarkably stable membrane domains at the plasma membrane but can also function as carriers in the exocytic and endocytic pathways. The apparently diverse functions of caveolae, including mechanosensing and lipid regulation, might be linked to their ability to respond to plasma membrane changes, a property that is dependent on their specialized lipid composition and biophysical properties.
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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.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Nucleic Acids Res
                Journal ID (iso-abbrev): Nucleic Acids Res
                Journal ID (publisher-id): nar
                Journal ID (hwp): nar
                Title: Nucleic Acids Research
                Publisher: Oxford University Press
                ISSN (Print): 0305-1048
                ISSN (Electronic): 1362-4962
                Publication date (Print): July 2008
                Publication date (Electronic): 16 June 2008
                Publication date PMC-release: 16 June 2008
                Volume: 36
                Issue: 12
                Pages: 4158-4171
                Affiliations
                Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599, USA
                Author notes
                *To whom correspondence should be addressed. +1 919 966 4383+1 919 966 5640 arjay@ 123456med.unc.edu
                Article
                Publisher ID: gkn342
                DOI: 10.1093/nar/gkn342
                PMC ID: 2475625
                PubMed ID: 18558618
                SO-VID: c08fd636-2d59-4d24-8a7d-f9b70f811d7d
                Copyright © © 2008 The Author(s)
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 2 April 2008
                Date revision received : 9 May 2008
                Date accepted : 12 May 2008
                Categories
                Subject: Survey and Summary

                ScienceOpen disciplines: Genetics
                Data availability:
                ScienceOpen disciplines: Genetics

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