Chemical modification of gene silencing oligonucleotides for drug discovery and development.

Gene silencing, the specific inhibition of unwanted gene expression by blocking mRNA activity, has long appeared to be an ideal strategy to leverage new genomic knowledge for drug discovery and development. But effective delivery has continuously been a limiting factor. In the past two decades, valuable progress has been made through the development of various chemically modified single-stranded antisense oligonucleotides, with improved properties such as enhanced stability, higher affinity and lower toxicity. Although short interfering RNA (siRNA) can provide better specificity and stronger efficacy by means of RNA interference (RNAi), in vivo delivery of siRNA often relies on plasmids or vectors, both of which present therapeutic safety risks. This review presents a brief history of gene silencing from PS-ODN through siRNA, introduces DNP-RNA--a more potent and easily delivered gene silencing platform--and compares its performance with that of siRNA and other AS-oligonucleotides.