Development and Modification of Decoy Oligodeoxynucleotides for Clinical Application

Abstract

AbstractSeveral chemical and structural modifications have been employed to improve the therapeutic effectiveness of oligodeoxynucleotides (ODNs), which largely depends on their stability against nucleases, specificity to the target nuclear factor, and efficient cellular and tissue uptake. Phosphorothioation of ODNs has been used in order to decrease their susceptibility to degradation by exo- and endonucleases. To overcome problems related to safety and the cost of production resulting from the fully chemical modified ODN, we developed a non-chemically modified decoy ODN, the ribbon-type decoy, by ligation of the extremities of two single phosphodiester strands. Moreover, we developed a chimera decoy with binding sequence for two different transcription factors. In this review we also discuss briefly the use of a biodegradable polyester as a carrier of ODN.ODN act as a decoy for specific transcription factors, and is used to attenuate the authentic cis–trans interaction, leading to removal of trans-factors from the endogenous cis-elements and subsequent modulation of gene expression. We developed an ODN that targets nuclear factor kappa B (NF-κB), which plays a pivotal role in the coordinated activation of inflammatory cytokines and expression of adhesion proteins; and chimera decoys for both NF-κB and Ets, and for both NF-κB and E2F. We discuss some studies on NF-κB decoy ODN and chimera decoys in cardiovascular and bone disease in mice, rat, and dog animal models, as well as results from some clinical trials.KeywordsBone diseaseCardiovascular diseaseDecoy oligodeoxynucleotideNF-κB