Decitabine‐Driven Foetal Haemoglobin Induction in Townes Mice and Human Erythroblasts

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.