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Abstract: SA-PO809

Advanced Disease Modeling of the Fabry Disease Cardiorenal Phenotype with Organoids from Patient-Derived Human-Induced Pluripotent Stem Cells

Session Information

Category: Genetic Diseases of the Kidneys

  • 1202 Genetic Diseases of the Kidneys: Non-Cystic

Authors

  • Reinelt, Anna, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
  • Laufer, Sandra D., Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
  • Wong, Milagros N., Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
  • Haas, Fabian, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
  • Foerster, Luise, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
  • Blomberg, Linda, Universitatsklinikum Koln, Koln, Nordrhein-Westfalen, Germany
  • Kurschat, Christine E., Universitatsklinikum Koln, Koln, Nordrhein-Westfalen, Germany
  • Wanner, Nicola, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
  • Puelles, Victor G., Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
  • Hansen, Arne, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
  • Huber, Tobias B., Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
  • Braun, Fabian, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
Background

Fabry disease is a multi-systemic lysosomal storage disorder resulting from mutations in the GLA gene. This complex lysosomal storage disorder can currently not be modelled accurately in animal models. Our project, therefore, aims at establishing advanced human in vitro systems to further our molecular understanding of the disease’s pathology. To establish these informative systems, we employ human induced pluripotent stem cells (hiPSC) of Fabry patients and differentiate them into disease-relevant organoid systems.

Methods

We reprogrammed hiPSC from primary urinary cells (PUCs) collected from Fabry patients with different mutations (classical, classical and chaperone amenable, late onset, unclear significance). Isogenic control lines were created by CRISPR Cas9 gene editing. Using published protocols, we differentiated these cell lines into kidney and heart organoids as well as engineered heart tissue (EHTs) using published protocols.

Results

We confirmed the loss of alpha-galactosiade A protein, enzyme activity and the accumulation of globotriaosylceramide in patient-derived hiPSC lines and organoids This phenotype did not impair the differentiation into organoids and EHTs. We established the treatment with enzyme replacement and, where applicable, chaperone therapy. Kidney organoids contained different nephron segments and confirmed the recently published pathologic accumulation of synuclein alpha in Fabry nephropathy. Heart organoids contracted and depicted several cardiac cell types including cardiomyocytes with sarcomeres and Z-Disc formation. Fabry EHTs contracted with reduced force and were prone to arrhythmias mirroring the clinical phenotype seen in Fabry patients.

Conclusion

We have established a novel unique discovery platform for human in vitro disease modelling to study Fabry disease. Ongoing experiments focus on single cell analyses of the established systems in combination with deep proteomic and spatial phenotyping combined with the application of available therapies.