Modification of Decoy Oligodeoxynucleotides to Achieve the Stability and Therapeutic Efficacy

Mariana      Kiomy Osako; Hironori      Nakagami; Ryuichi      Morishita

Abstract

The decoy oligodeoxynucleotide (ODN) serves as a decoy sequence for a target transcription factor, then inhibiting its binding to the authentic sequence at the promoter, and consequently hinders the gene expression. ODNs should be properly up taken by the cell and tissue, be specific for one nuclear factor, and be stable against intracellular and serum nucleases. Since phosphodiester oligos are easily degradated by nucleases, chemical modification such as phosphorothioation, and structural modification by ligation of the extremities of two single-strand phosphodiester sequence resulting in a dumbbell shaped ODN (Ribbon-type decoy ODN) are performed to increase the stability of ODNs. In combination, phosphorothioation of specific regions in Ribbon-type decoy has further increased its stability, and the introduction of saturated hydrocarbon polymer spacer linking the two double strands also improved the stability and reduced the production cost. The cellular delivery has been optimized by using the biodegradable polymer D,L-lactide-co-glycolide (PLGA) as a carrier to ODN.

The nuclear factor-kappa B (NF-κB) is a convergent point of different pathways, with main role in many pathologies, and poses as an ideal target for decoy ODN strategy. Following this we have designed ODN targeting NF-κB, and in this review, we are going to discuss the various modification performed in an attempt to improve the ODN efficacy, and some promising pre-clinical data and clinical trials using NF-κB decoy ODN.

Keywords: Decoy oligodeoxynucleotides nuclear factor κB, Therapeutic Efficacy, (Ribbon-type decoy ODN), phosphorothioation

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