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Modeling the therapeutic efficacy of NF?B synthetic decoy oligodeoxynucleotides (ODNs).

ABSTRACT: BACKGROUND:Transfection of NF ?B 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 ?B. 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 ?B regulatory networks displaying oscillatory temporal dynamics, can be used to predict quantitatively the dependence of therapeutic efficacy of NF ?B 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 ?B regulatory networks is most sensitive to adding NF ?B 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.

SUBMITTER: Wang Z

PROVIDER: S-EPMC5791368 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Modeling the therapeutic efficacy of NFκB synthetic decoy oligodeoxynucleotides (ODNs).

Wang Zhipeng Z Potoyan Davit A DA Wolynes Peter G PG

BMC systems biology 20180130 1

<h4>Background</h4>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.<h4>Results</h4>In this work, we show how a systems pharmacology model of NF κB regulatory networks displaying oscillatory temporal dynamics, ...[more]

PMID: 29382384

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Project description:Rationale: Macrophages play multi-dimensional roles in hepatic fibrosis. Studies have implicated Notch signaling mediated by the transcription factor RBP-J in macrophage activation and plasticity. Additionally, we have previously shown that myeloid-specific disruption of RBP-J can ameliorate hepatic fibrosis in mice. Accordingly, we next asked whether blocking Notch signaling in macrophages could serve as a therapeutic strategy to treat hepatic fibrosis. In this study, we used a combination of transcription factor decoy oligodeoxynucleotides (ODNs) and exosomes to test this possibility. Methods: Hairpin-type decoy oligodeoxynucleotides (ODNs) were designed for the transcription factor RBP-J. The effects of RBP-J decoy ODNs on Notch signaling were evaluated by western blot, quantitative RT-PCR, luciferase reporter assays, and electrophoretic mobility shift assays. ODNs were loaded into HEK293T-derived exosomes by electroporation. A hepatic fibrosis mouse model was established by the intraperitoneal injection of carbon tetrachloride or bile duct ligation. Mice with hepatic fibrosis were administered exosomes loaded with RBP-J decoy ODNs via tail vein injection. The in vivo distribution of exosomes was analyzed by fluorescence labeling and imaging. Liver histology was examined using hematoxylin and eosin, Sirius red, and Masson staining, as well as immunohistochemical staining for Col1α1 and αSMA. Results: We found that RBP-J decoy ODNs could be efficiently loaded into exosomes and inhibit the activation of Notch signaling. Furthermore, exosomes administered via the tail vein were found to be primarily taken up by hepatic macrophages in mice with liver fibrosis. Importantly, RBP-J decoy ODNs delivered by exosomes could efficiently inhibit Notch signaling in macrophages and ameliorate hepatic fibrosis in mice. Conclusions: Combined, our data showed that the infusion of exosomes loaded with RBP-J decoy ODNs represents a promising therapeutic strategy for the treatment of hepatic fibrosis.

Dataset Information

Modeling the therapeutic efficacy of NF?B synthetic decoy oligodeoxynucleotides (ODNs).

Publications

Modeling the therapeutic efficacy of NFκB synthetic decoy oligodeoxynucleotides (ODNs).

Similar Datasets

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