Antisense oligonucleotides: from design to therapeutic application.
1. 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. 2. 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. 3. 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.
Chan
Jasmine H P
JH
Department of Pharmacology, Yong Loo Lin School of Medicine and Immunology Program, National University of Singapore, Singapore.
Lim
Shuhui
S
Wong
W S Fred
WS
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism*; D051152:Clusterin / Q000235:genetics / Q000378:metabolism; D020868:Gene Silencing; D018390:Gene Targeting / Q000639:trends; D006801:Humans; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D009690:Nucleic Acid Conformation; D009838:Oligodeoxyribonucleotides; D016376:Oligonucleotides, Antisense / Q000138:chemical synthesis / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D012264:Ribonucleotide Reductases / Q000235:genetics / Q000378:metabolism; D013873:Thionucleotides / Q000138:chemical synthesis / Q000235:genetics / Q000378:metabolism
D000970:Antineoplastic Agents; C495242:CLU protein, human; D051152:Clusterin; C503781:OGX-011; D009838:Oligodeoxyribonucleotides; D016376:Oligonucleotides, Antisense; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D013873:Thionucleotides; C464617:GTI2040; C408162:oblimersen; D012264:Ribonucleotide Reductases; C108427:ribonucleotide reductase R2 subunit