Journal Article Epublish
PubMed: 40761187 DOI: 10.1002/jha2.70120
Decitabine-Driven Foetal Haemoglobin Induction in Townes Mice and Human Erythroblasts.
EJHaem 6(4):e70120
Authors: Ariadna Carol Illa, Desmond Wai Loon Chin, Martha Clark, Jesper Petersen, Søren Skov, Andreas Glenthøj, Carsten Dan Ley
Affiliations
- Rare Disease Research Global Drug Discovery Novo Nordisk A/S Måløv Denmark. Department of Veterinary and Animal Sciences Faculty of Health and Medical Sciences University of Copenhagen Copenhagen Denmark.
- Rare Disease Research Global Drug Discovery Novo Nordisk Research & Development US, Inc. Boston Massachusetts USA.
- Danish Red Blood Cell Center Department of Hematology Copenhagen University Hospital - Rigshospitalet Copenhagen Denmark.
- Department of Veterinary and Animal Sciences Faculty of Health and Medical Sciences University of Copenhagen Copenhagen Denmark.
- Department of Clinical Medicine University of Copenhagen Copenhagen Denmark.
- Rare Disease Research Global Drug Discovery Novo Nordisk A/S Måløv Denmark.
Abstract
Background
Induction of foetal haemoglobin (HbF) is a clinically validated approach to modulate the severity of sickle cell disease (SCD). This manuscript evaluates the efficacy of decitabine, a DNA methyltransferase (DNMT) inhibitor, in inducing HbF in healthy human erythroblasts and Townes mice, which are well-established systems modelling SCD.
Methods
Healthy human erythroblasts were treated with decitabine, and HbF induction was measured. Townes sickle cell mice were administered decitabine for 12 weeks, and various haematological parameters were assessed.
Results
In healthy human erythroblasts, decitabine treatment resulted in a significant increase in the fraction of HbF-rich cells (F-cells), accompanied by elevated HbF protein levels. The HbF induction was superior to that achieved with hydroxyurea, the primary therapy for SCD. In Townes mice, the maximal response was observed after 12 weeks of dosing, with an increase in both HbF protein and F-cells, alongside reduced red blood cell and reticulocyte counts. Additionally, we observed changes in other haematological parameters, such as increased mean corpuscular volume and mean corpuscular haemoglobin. However, the HbF induction observed in the mice was modest relative to known human responses. No marked improvements in SCD-related biomarkers such as haemolysis or liver function were detected, suggesting that the mouse model may not fully capture the extent of phenotype improvement. Histopathological examination revealed no adverse effects on bone marrow cellularity or morphology and indicated a protective effect on liver tissue integrity.
Conclusion
Our results demonstrate that decitabine induces HbF in a dose-dependent manner in both in vitro and in vivo settings, highlighting the complexity of HbF induction as a treatment for SCD and underscoring the need for further refinement of this model for SCD therapy research. Trial Registration: The authors have confirmed clinical trial registration is not needed for this submission.
MeSH
Cells, Erythroblasts, Anemia, Sickle Cell, Decitabine, Liver, Hemolysis, Therapeutics