2cSysBioMed, Contra, Switzerland; Department of Clinical Medicine, University of Bergen, Bergen, Norway.
Department of Clinical Medicine, University of Bergen, Bergen, Norway; Department of Medicine, Haukeland University Hospital, Bergen, Norway.
Kidney Int. 2023 Oct;104(4):803-819. doi: 10.1016/j.kint.2023.06.029. Epub 2023 Jul 5.
Fabry disease is a rare disorder caused by variations in the alpha-galactosidase gene. To a degree, Fabry disease is manageable via enzyme replacement therapy (ERT). By understanding the molecular basis of Fabry nephropathy (FN) and ERT's long-term impact, here we aimed to provide a framework for selection of potential disease biomarkers and drug targets. We obtained biopsies from eight control individuals and two independent FN cohorts comprising 16 individuals taken prior to and after up to ten years of ERT, and performed RNAseq analysis. Combining pathway-centered analyses with network-science allowed computation of transcriptional landscapes from four nephron compartments and their integration with existing proteome and drug-target interactome data. Comparing these transcriptional landscapes revealed high inter-cohort heterogeneity. Kidney compartment transcriptional landscapes comprehensively reflected differences in FN cohort characteristics. With exception of a few aspects, in particular arteries, early ERT in patients with classical Fabry could lastingly revert FN gene expression patterns to closely match that of control individuals. Pathways nonetheless consistently altered in both FN cohorts pre-ERT were mostly in glomeruli and arteries and related 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 reemerged despite ERT. Inferring an ERT-resistant genetic module of expressed genes identified 69 drugs for potential repurposing matching the proteins encoded by 12 genes. Thus, we identified and cross-validated ERT-resistant gene product modules that, when leveraged with external data, allowed estimating their suitability as biomarkers to potentially track disease course or treatment efficacy and potential targets for adjunct pharmaceutical treatment.
法布里病是一种由α-半乳糖苷酶基因突变引起的罕见疾病。在一定程度上，法布里病可以通过酶替代疗法（ERT）进行治疗。通过了解法布里肾病（FN）的分子基础和 ERT 的长期影响，我们旨在为潜在疾病生物标志物和药物靶点的选择提供一个框架。我们从 8 名对照个体和 2 个独立的 FN 队列中获得了活检样本，每个队列包含 16 名个体，这些个体在接受 ERT 治疗前和治疗后长达 10 年内进行了活检，然后进行了 RNAseq 分析。将基于途径的分析与网络科学相结合，计算了四个肾单位的转录景观，并将其与现有的蛋白质组和药物靶点相互作用组数据进行了整合。比较这些转录景观揭示了高度的组间异质性。肾单位转录景观全面反映了 FN 队列特征的差异。除了少数方面，特别是动脉，经典法布里病患者的早期 ERT 可以持久地将 FN 基因表达模式恢复为与对照个体非常接近的模式。然而，在 ERT 前的两个 FN 队列中，一致改变的途径主要在肾小球和动脉中，与相同的生物学主题相关。虽然肾小球中的角化相关过程对 ERT 敏感，但大多数改变，如转运体活性和对刺激的反应，尽管接受了 ERT 治疗，但仍然失调或重新出现。推断出表达基因的 ERT 抗性基因模块，鉴定了 69 种潜在再利用的药物，这些药物与 12 个基因编码的蛋白质相匹配。因此，我们确定并交叉验证了 ERT 抗性基因产物模块，当与外部数据结合使用时，可以评估它们作为生物标志物的适用性，以潜在地跟踪疾病过程或治疗效果，以及作为辅助药物治疗的潜在靶点。
