Results, Potential Impacts, and Future Uptake
Overview of Results
The HYPOXIA project delivered substantial advancements in the understanding of erythropoietin (EPO) gene regulation and its clinical implications in hereditary erythrocytosis:
Identification of Novel Pathogenic EPO Variants
We identified three previously unrecognized non-coding variants in the EPO gene (c.-252C→T, c.14–28T→C, and c.14–26A→G) in patients with unexplained erythrocytosis. These variants were shown to be pathogenic through genetic segregation and comprehensive functional validation.
Mechanistic Insights into EPO Dysregulation
Through reporter assays and stem cell–derived models, we demonstrated that these variants dysregulate EPO transcription by altering hypoxia responsiveness and transcription factor binding, particularly involving GATA factors and HIF-2α.
Development of iPSC-Derived Hepatocyte Models
We successfully developed patient-specific hepatocyte-like cells from iPSCs to model hepatic EPO production in vitro—an innovative platform with applications in disease modeling, drug screening, and future gene therapy validation.
Biochemical and Functional Characterization of Circulating EPO
Using isoelectric focusing and bioactivity assays, we demonstrated that patients express a fetal liver–like EPO isoform with enhanced receptor activity—a functional gain-of-function phenotype not detectable by conventional EPO assays.
Potential Scientific, Clinical, and Societal Impacts
Improved Diagnostics for Rare Erythrocytosis
Our results provide the basis for more accurate genetic screening, especially in idiopathic cases, and update current clinical workflows that rely only on serum EPO concentration.
Platform for Personalized Medicine and Therapy Testing
The iPSC-based model is adaptable to screen therapeutic responses or test correction strategies, accelerating preclinical research for personalized therapies.
New Avenues for Biotechnological Innovation
The discovery of a natural, hyperactive EPO isoform opens opportunities for developing next-generation biologics with enhanced efficacy and potentially reduced side effects.
Key Needs to Ensure Further Uptake and Success
To ensure sustained uptake and broad impact, the following enablers are identified:
Further Research and Demonstration
Longitudinal studies to assess clinical outcomes in variant carriers.
Preclinical validation of hepatic EPO as a therapeutic candidate or gene therapy target.
Comparative studies of iPSC-derived EPO models across tissue types (kidney, liver).
Commercialisation and Market Access
Tech transfer strategies to protect and develop applications of hepatic-like EPO isoforms.
Partnerships with biotech firms to explore therapeutic formulation or delivery.
Business model development for licensing the iPSC-derived disease models.
IPR and Regulatory Support
Support to file patents for novel EPO variants and bioactivity assays.
Engagement with EMA and other regulators to integrate new biomarker-based diagnostics.
Standardisation and Diagnostics Integration
Inclusion of qualitative EPO assays (e.g. isoelectric focusing) in EU diagnostic standards.
Expansion of clinical genetic panels to non-coding regulatory regions.
Internationalisation and Collaboration
Promote data sharing through the European Reference Networks (ERNs) and International Rare Disease Research Consortium (IRDiRC).
Foster collaboration with cord blood banks and biobanks to advance glycosylation research.
The HYPOXIA project has not only addressed a clinically relevant scientific question but also laid the foundation for tangible diagnostic, therapeutic, and commercial innovations. With the right enablers, these results can drive lasting impact in rare disease healthcare, biopharmaceutical development, and personalised medicine.
