ANTISENSE OLIGONUCLEOTIDES: FROM DESIGN TO THERAPEUTIC APPLICATION

Authors: Chan, Jasmine HP; Lim, Shuhui; Wong, WS Fred

Source: Clinical and Experimental Pharmacology and Physiology, Volume 33, Numbers 5-6, May/June 2006 , pp. 533-540(8)

Publisher: Blackwell Publishing

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Abstract:

SUMMARY

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An antisense oligonucleotide (ASO) is a short strand of deoxyribonucleotide analogue that hybridizes with the complementary mRNA in a sequence-specific manner via Watson–Crick base pairing. Formation of the ASO–mRNA heteroduplex either triggers RNase H activity, leading to mRNA degradation, induces translational arrest by steric hindrance of ribosomal activity, interferes with mRNA maturation by inhibiting splicing or destabilizes pre-mRNA in the nucleus, resulting in downregulation of target protein expression.

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The ASO is not only a useful experimental tool in protein target identification and validation, but also a highly selective therapeutic strategy for diseases with dysregulated protein expression.

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In the present review, we discuss various theoretical approaches to rational design of ASO, chemical modifications of ASO, ASO delivery systems and ASO-related toxicology. Finally, we survey ASO drugs in various current clinical studies.

Keywords: antisense oligonucleotide design; cell-penetrating peptide; dendrimer; gapmer antisense oligonucleotide; liposome; locked nucleic acid; peptide nucleic acid; phosphoroamidate morpholino oligomer; phosphorothioate; RNase H

Document Type: Research article

DOI: 10.1111/j.1440-1681.2006.04403.x

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