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

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Background: Fabry nephropathy (FN) is a rare disorder caused by mutations in the alpha-galactosidase A gene that can, to a certain degree, be managed with enzyme replacement therapy (ERT). Via understanding the molecular basis of FN and ERT's long-term impact, we aim at providing a framework allowing selection of biomarkers and drug-targets. Methods: Obtained from controls and two independent FN-cohorts, mRNA-isolates from archival kidney biopsies taken prior and up to 10 years of ERT, were subjected to RNAseq. Combining pathway-centered analyses with network-science allowed computation of transcriptional landscapes from glomeruli, proximal tubuli, distal tubuli and arteries and integration with existing proteome, interactome and drug::target data. Results: Comparing transcriptional landscapes per cohort revealed high inter-cohort heterogeneity. Especially, with timely treatment initiation, FN seemed well controlled via ERT. Pathways consistently altered in both FN-cohorts pre-ERT vs. N_CTRLs were limited to glomeruli and arteries and commonly pertained to the same biological themes. While keratinization-related processes in glomeruli were sensitive to ERT, a majority of alterations, such as transporter activity and responses to stimuli, remained dysregulated or remerged despite of ERT. Inferring an ERT-resistant genetic module on this basis identified targets suitable for drug repurposing. Conclusions: Kidney compartments' transcriptional landscapes comprehensively reflected differences in FN-cohort characteristics. With the exception of few key aspects, in particular concerning arteries, early ERT in classical Fabry patients could lastingly revert FN kidney-compartments' molecular state to closely match N_CTRLs. Thus, we identified and cross-validated ERT-resistant modules that, when leveraged with external data, allowed estimating their suitability as biomarkers and potential targets for adjunct treatment. Funding: Commercial Support - Shire/Takeda, Sanofi Aventis, Government Support - Non-U.S.

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