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Abstract: SA-PO109

Novel Exosome-Based Therapeutics Targeting NF-kB/p65 for AKI

Session Information

  • AKI: Mechanisms - III
    November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Author

  • Choi, Chulhee, ILIAS Biologics Inc., Daejeon, Korea (the Republic of)
Background

Either systemic or local inflammation-induced by infection or ischemic reperfusion is the key pathophysiological event driving sepsis associated (SA)- and cardiac surgery-associated (CSA)-AKI development. NF-kB signaling pathway plays a pivotal role in driving inflammation in both SA- and CSA-AKI. Effective/specific inhibition of NF-kB signaling pathway may ameliorate the course of SA- and CSA-AKI. Recent advancements in nano-technology made it feasible to specifically target NF-kB signaling. The intracellular delivery of protein API (NF-kB inhibitor) with exosome as DDS is an attractive approach for tackling NF-kB signaling in the target cells without off-target effect in both SA- and CSA-AKI.

Methods

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Results

Utilizing ILIAS Bio’s EXPLOR® (EXosome engineering for Protein Loading via Optically Reversible protein-protein interactions) technology, we have developed Exo-srIκB with srIκB as API which is a constitutively active form of IκBα with a prolonged half-life in the target cells. Exo-srIκB exhibits anti-inflammation function via specific inhibition of stimuli-induced NF-kB/p65 activation. In the septic mice, the treatment of Exo-srIκB inhibits systemic inflammation and improves survival with the amelioration of SA-AKI. In the renal ischemic-reperfusion mice, the treatment of Exo-srIκB alleviates IRI-AKI by down-regulating NF-kB signaling and ameliorating inflammation/apoptosis in the ischemic injured kidney.

Conclusion

The direct intracellular delivery of immunosuppressive protein (srIκB) into target cells using exosomes can be used as a promising therapeutic approach for both SA- and CSA-AKI. The therapeutic potential of Exo-srIκB in both SA- and CSA-AKI should be explored further by clinical trials. Via GLP-toxicology and safety pharmacology studies, it has been determined that Exo-srIκB has no toxicity with minimum 20 folds safety margin compared to the efficacy dose, and based on repeated dose study, both NOAEL and HED were determined, which grant Exo-srIκB first-in-human (FIH) study.