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Kidney Week

Abstract: SA-PO626

Use of Urinary Exosomes to Confirm Pharmacological Activity of CXA-10 on Nrf2 and Heat Shock Response Gene Expression in the Kidney of Patients with CKD

Session Information

  • Pharmacology
    October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

  • 1700 Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

Authors

  • Garner, Rachel, Complexa, Inc., Berwyn, Pennsylvania, United States
  • Levonen, Anna-Liisa, University of Eastern Finland, Kuopio, Finland
  • Chieffo, Carla, Complexa, Inc. Consultant, Berwyn, Pennsylvania, United States
  • Debouck, Christine M., Ardennes Biosciences LLC, Wayne, Pennsylvania, United States
  • Schopfer, Francisco J., University of Pittsburgh, Pittsburgh, Pennsylvania, United States
  • Jorkasky, Diane K., Complexa, Inc., Berwyn, Pennsylvania, United States
Background

CXA-10 is an electrophilic nitrated fatty acid being developed for focal segmental glomerular sclerosis. In animal studies, CXA-10 modulated several pathways including activation of nuclear factor E2-related factor 2 (Nrf2) and heat shock response (HSR). Urinary exosomes are small cell-derived vesicles shed from kidney cells that carry mRNA and proteins. Genetic material in urinary exosomes reflects gene activation in the kidney. The purpose of this study was to examine the ability of CXA-10 to induce Nrf2- and HSR-dependent gene expression in blood and kidney of subjects with chronic kidney disease (CKD).

Methods

This was a multicenter, open-label, single-dose study of CXA-10 in subjects with moderate and severe CKD. Four subjects received a 1-hour infusion of 0.34 mg/kg and 8 subjects received a 1-hour infusion of 0.68 mg/kg CXA-10. Gene expression assessments were conducted from predose to 96 hours postdose as the time course of responses was unknown. Whole blood and urine samples were collected for analysis of target genes by qRT-PCR in isolated PBMCs and exosomes, respectively. Target genes were from the Nrf2 pathway, NAD(P)H quinone dehydrogenase 1 (NQO1) and Heme Oxygenase 1 (HMOX-1) and the heat shock pathway, Heat Shock Protein Family A and 1B (HSPA1A/B).

Results

Gene expression increased after CXA-10 dosing for all target genes. Maximum gene expression per subject showed a dose-response relationship for NQO1 and HSP1A/B in both PBMCs and urinary exosomes. Gene expression response, defined as ≥3-fold increase from baseline, was exhibited in 10 subjects (83.3%) for ≥1 target gene. PBMC gene expression response was observed in 8 subjects (66.7%) and urinary exosome gene expression in 6 subjects (50%). HSPA1A/B showed the highest level of induction in both PBMCs and urinary exosomes.

Conclusion

A single IV dose of CXA-10 increases cellular protective Nrf2- and HSR-related genes in subjects with CKD. This study demonstrates the first human translation of the pharmacological actions of CXA-10 that have been previously characterized in vitro and in animal models. To our knowledge, this is the first use of urinary exosomes to demonstrate the pharmacological action in the target organ of a novel drug in clinical development.

Funding

  • Commercial Support