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Overcoming biological barriers to in vivo efficacy of antisense oligonucleotides

Published online by Cambridge University Press:  23 March 2009

Paul J. White ,
Frank Anastasopoulos ,
Colin W. Pouton  and
Ben J. Boyd
Paul J. White*
Affiliation:
Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
Frank Anastasopoulos
Affiliation:
Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia. Clinical Vision Research Australia, Victorian College of Optometry, Carlton, Victoria 3053, Australia.
Colin W. Pouton
Affiliation:
Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
Ben J. Boyd
Affiliation:
Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
*
*Corresponding author: Paul J. White, Medicinal Chemistry and Drug Action, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia. Tel: +613 99039074; Fax: +613 99039638; E-mail: paul.white@pharm.monash.edu.au
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Abstract

Antisense oligonucleotides as a therapeutic platform have been slow to progress since the approval of the first antisense drug in 1998. Recently, there have been several examples of convincing antisense interventions in animal models and promising clinical trial data. This review considers the factors determining the success of antisense oligonucleotides as therapeutic agents. In order to produce target knockdown after systemic delivery, antisense oligonucleotides must avoid nuclease degradation, reticuloendothelial-system uptake and rapid renal excretion, and extravasate to the target cell type outside the vasculature. They then must enter the target cell, and escape the endosome–lysosome pathway so as to be free to interact with the target mRNA. We consider the significance of these limiting factors based on the literature and our own experience using systemic administration of antisense oligonucleotides.

Type
Review Article
Information
Expert Reviews in Molecular Medicine , Volume 11 , July 2009 , e10
Copyright
Copyright © Cambridge University Press 2009

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References

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Crooke, S., ed. (2008) Antisense Drug Technology; Principles, Strategies and Applications, CRC Press, Boca Raton, FL, USAGoogle Scholar
Rayburn, E.R. and Zhang, R. (2008) Antisense, RNAi, and gene silencing strategies for therapy: mission possible or impossible? Drug Discovery Today 13, 513-521Google Scholar
Juliano, R. et al. (2008) Mechanisms and strategies for effective delivery of antisense and siRNA oligonucleotides. Nucleic Acids Research 36, 4158-4171Google Scholar
Crooke, S., ed. (2008) Antisense Drug Technology; Principles, Strategies and Applications, CRC Press, Boca Raton, FL, USAGoogle Scholar
Rayburn, E.R. and Zhang, R. (2008) Antisense, RNAi, and gene silencing strategies for therapy: mission possible or impossible? Drug Discovery Today 13, 513-521Google Scholar
Juliano, R. et al. (2008) Mechanisms and strategies for effective delivery of antisense and siRNA oligonucleotides. Nucleic Acids Research 36, 4158-4171Google Scholar