Modulation of gene expression by antisense and antigene oligodeoxynucleotides and small interfering RNA. Exp Opin Drug Deliv

University of Tennessee Health Science Center, Department of Pharmaceutical Sciences, 26 South Dunlap Street, Feurt Bldg RM 406, Memphis, TN 38163, USA.
Expert Opinion on Drug Delivery (Impact Factor: 4.84). 02/2005; 2(1):3-28. DOI: 10.1517/17425247.2.1.3
Source: PubMed


Antisense oligodeoxynucleotides, triplex-forming oligodeoxynucleotides and double-stranded small interfering RNAs have great potential for the treatment of many severe and debilitating diseases. Concerted efforts from both industry and academia have made significant progress in turning these nucleic acid drugs into therapeutics, and there is already one FDA-approved antisense drug in the clinic. Despite the success of one product and several other ongoing clinical trials, challenges still exist in their stability, cellular uptake, disposition, site-specific delivery and therapeutic efficacy. The principles, strategies and delivery consideration of these nucleic acids are reviewed. Furthermore, the ways to overcome the biological barriers are also discussed so that therapeutic concentrations at their target sites can be maintained for a desired period.

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Available from: Ram I Mahato, Aug 11, 2015
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    • "The former is an antisense strategy by which antisense ODNs bind (at least in theory) their complementary mRNAs (Opalinska and Gewirtz 2002), thereby leading to gene silencing by either the inhibition of the ribosome-mediated translation process (Fig. 1, pathway 3a) or by means of the nuclear enzyme ribonuclease H (RNase H) that degrades mRNAs once coupled to DNAs (Fig. 1, pathway 3b). The latter strategy involves triplex forming oligonucleotides (TFOs) that specifically bind the major groove of the genomic DNA in correspondence of either the coding or the regulatory regions of target genes thus forming a triplex structure that inhibits transcription (Fig. 1, pathway 3c) (Mahato et al. 2005; Miller et al. 2008). Of note, several clinical trials on the use of antisense ODNs are currently underway and formivirsen (Vitravene Ò , ISIS "
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    ABSTRACT: Gene delivery is the science of transferring genetic material into cells by means of a vector to alter cellular function or structure at a molecular level. In this context, a number of nucleic acid-based drugs have been proposed and experimented so far and, as they act on distinct steps along the gene transcription– translation pathway, specific delivery strategies are required to elicit the desired outcome. Cationic lipids and polymers, collectively known as non-viral deliv-ery systems, have thus made their breakthrough in basic and medical research. Albeit they are promising alternatives to viral vectors, their therapeutic applica-tion is still rather limited as high transfection efficien-cies are normally associated to adverse cytotoxic side effects. In this scenario, drawing inspiration from processes naturally occurring in vivo, major strides forward have been made in the development of more effective materials for gene delivery applications. Specifically, smart vectors sensitive to a variety of physiological stimuli such as cell enzymes, redox status, and pH are substantially changing the land-scape of gene delivery by helping to overcome some of the systemic and intracellular barriers that viral vectors naturally evade. Herein, after summarizing the state-of-the-art information regarding the use of nucleic acids as drugs, we review the main bottlenecks still limiting the overall effectiveness of non-viral gene delivery systems. Finally, we provide a critical outline of emerging stimuli-responsive strategies and discuss challenges still existing on the road toward conceiving more efficient and safer multifunctional vectors. Introduction to gene therapy and gene delivery
    Journal of Nanoparticle Research 03/2013; 15(3):1-27. DOI:10.1007/s11051-013-1523-7 · 2.18 Impact Factor
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    • "For example, phosphorothioate (PS) linkage is one of the simplest modifications of the siRNA backbone. Studies showed that toxicity and loss of silencing activity could pose a hurdle when phosphorothioate-modified siRNAs are employed (Manoharan 2004, Mahato 2005). A better alternative to backbone modification is the boranophosphonate linkage, which is more effective at silencing than phosphorothioate siRNAs, and is 10 times more nuclease resistant in comparison with unmodified siRNAs. "

    Gene Therapy - Developments and Future Perspectives, 06/2011; , ISBN: 978-953-307-617-1
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    • "Therefore, oligonucleotides may be used for the control of gene expression (Helene, 1991, 1994). There are three main approaches for the use of oligonucleotides as modulators of gene expression: the antigene, antisense, and more recently, small interfering RNA (siRNA), all target specific nucleic acid structures (Mahato et al., 2005). In the antigene strategy, a single strand binds to the major groove of a DNA duplex, forming a triple helix (Soyfer and Potaman, 1996) that inhibits transcription, by competing with the binding of proteins that activate the transcriptional machinery (Helene, 1994; Maher et al., 1989). "
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    ABSTRACT: The main focus of our investigations is to further our understanding of the physicochemical properties of nucleic acid structures. We report on a thermodynamic approach to study the reaction of a variety of intramolecular nucleic acid structures with their respective complementary strands. Specifically, we have used a combination of isothermal titration (ITC) and differential scanning calorimetry (DSC) and spectroscopy techniques to determine standard thermodynamic profiles for the reaction of a triplex, G-quadruplex, hairpin loops, pseudoknot, and three-arm junctions with their complementary strands. Reaction enthalpies are measured directly in ITC titrations, and compared with those obtained indirectly from Hess cycles using DSC unfolding data. All reactions investigated yielded favorable free energy contributions, indicating that each single strand is able to invade and disrupt the corresponding intramolecular DNA structure. These favorable free energy terms are enthalpy-driven, resulting from a favorable compensation of exothermic contributions due to the formation of additional base-pair stacks in the duplex product, and endothermic contributions, from the disruption of base stacking contributions of the reactant single strands. The overall results provide a thermodynamic approach that can be used in the targeting of nucleic acids, especially the secondary structures formed by mRNA, with oligonucleotides for the control of gene expression.
    Methods in enzymology 01/2011; 492:1-26. DOI:10.1016/B978-0-12-381268-1.00013-6 · 2.09 Impact Factor
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