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
- Genetic Diseases of the Kidneys: Non-Cystic - 1
October 22, 2020 | Location: On-Demand
Abstract Time: 10:00 AM - 12:00 PM
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.