History of Research on Antisense Oligonucleotide Analogs

Abstract

In the search for novel therapeutics, antisense oligonucleotide (ASO) analogs have been a major focus of research for over 40 years. They use the antisense strategy, namely they have a nucleic acid base sequence that is complementary to a portion of a specific mRNA that is produced in the cell, or to a viral RNA, in order to selectively inhibit gene expression. Oligonucleotides need to be chemically modified to stabilize them against hydrolysis by endogenous nucleases. Until now several phosphorothioate (PS) oligonucleotide analogs have been approved by the FDA for human use. This article seeks to provide a history of this subject to date.

Potential Use of Multiple Antisense Oligonucleotide Analogs for Cancer Prevention and Therapy

“…We intend to have the ASO synthesized almost certainly as the phosphorothioate (PS) analogs that seem to have been the most successful type. However, there are competing claims by the users of various analogs, 1 , and we hope soon to have the results of comparative molecular dynamics studies 6 of the duplexation of the most commonly used analogs, 3 , which hopefully can guide us as to which chemically modified analog is preferable.…”

“…As indicated at the conclusion of a historical review of antisense oligo applications, 1 antisense should be a way to tackle complex genetic diseases like cancer. In general, it is known that to enable a tumor to grow, three mutations are required 2 : 1.…”