Modeling the therapeutic efficacy of N F Κ B synthetic decoy oligodeoxynucleotides (ODNs)

Abstract

Background: Transfection of NF ΚB synthetic decoy Oligodeoxynucleotides (ODNs) has been proposed as a promising therapeutic strategy for a variety of diseases arising from constitutive activation of the eukaryotic transcription factor NF ΚB. The decoy approach faces some limitations under physiological conditions notably nuclease-induced degradation. Results: In this work, we show how a systems pharmacology model of NF ΚB regulatory networks displaying oscillatory temporal dynamics, can be used to predict quantitatively the dependence of therapeutic efficacy of NF ΚB synthetic decoy ODNs on dose, unbinding kinetic rates and nuclease-induced degradation rates. Both deterministic mass action simulations and stochastic simulations of the systems biology model show that the therapeutic efficacy of synthetic decoy ODNs is inversely correlated with unbinding kinetic rates, nuclease-induced degradation rates and molecular stripping rates, but is positively correlated with dose. We show that the temporal coherence of the stochastic dynamics of NF ΚB regulatory networks is most sensitive to adding NF ΚB synthetic decoy ODNs having unbinding time-scales that are in-resonance with the time-scale of the limit cycle of the network. Conclusions: The pharmacokinetics/pharmacodynamics (PK/PD) predicted by the systems-level model should provide quantitative guidance for in-depth translational research of optimizing the thermodynamics/kinetic properties of synthetic decoy ODNs.