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Kidney Week

Abstract: PO1606

Systems Analyses of Renal Fabry Transcriptome and Response to Enzyme Replacement Therapy (ERT) Identifies a Cross-Validated and Druggable ERT-Resistant Module

Session Information

Category: Genetic Diseases of the Kidneys

  • 1002 Genetic Diseases of the Kidneys: Non-Cystic

Authors

  • Eikrem, Oystein, University of Bergen, Bergen, Norway
  • Delaleu, Nicolas, 2C SysBioMed, Contra, Switzerland
  • Strauss, Philipp, University of Bergen, Bergen, Norway
  • Sekulic, Miroslav, UH Cleveland Medical Center, Cleveland, Ohio, United States
  • Tøndel, Camilla, Haukeland University Hospital, Bergen, Norway
  • Leh, Sabine, Haukeland University Hospital, Bergen, Norway
  • Svarstad, Einar, University of Bergen, Bergen, Norway
  • Skrunes, Rannveig, Haukeland University Hospital, Bergen, Norway
  • Nowak, Albina, University Hospital of Zurich, Zurich, Switzerland
  • Rusu, Elena-Emanuela, Fundeni Clinical Institute, Bucharest, Romania
  • Osman, Tarig Al-Hadi, University of Bergen, Bergen, Norway
  • Marti, Hans-Peter, University of Bergen, Bergen, Norway

Group or Team Name

  • Renal Research Group Bergen
Background

Fabry nephropathy (FN) is caused by mutations in the α-galactosidase A gene and can be managed with ERT. Via understanding the molecular basis of FN and long-term ERT impact, we aim at a framework for selection of biomarkers/drug-targets.

Methods

Obtained from normal controls and two independent FN-cohorts, mRNA-isolates from archival kidney biopsies (n=41) taken prior and up to 10 years of ERT were subjected to RNAseq and partly IHC. Combining pathway-centered analyses with network-science allowed computation of transcriptional landscapes from glomeruli, proximal/distal tubuli & arteries and integration with existing proteome and drug::target data.

Results

Despite inter-cohort heterogeneity, FN seemed well controlled, esp. via early introduced ERT. Pathways consistently altered in both FN-cohorts pre-ERT vs. controls were limited to glomeruli and arteries and commonly pertained to same biological themes. While glomerular keratinization-related processes were ERT sensitive, a majority of alterations, such as transporter activity and responses to stimuli, remained dysregulated or remerged despite ERT. Inferring an ERT-resistant genetic module on this basis identified targets suitable for drug repurposing (Figure 1).

Conclusion

Transcriptional landscapes of kidney compartments reflected differences in FN-cohorts. ERT can revert FN molecular state to closely match controls. We identified and cross-validated ERT-resistant modules, when leveraged with external data, allowed estimating their suitability as biomarkers and targets for adjunct treatment.

Figure 1. Target::Target::Drug interactome. Node color target: green=glomerular target, blue=arterial target.

Funding

  • Government Support - Non-U.S.