Drugs Repurposing of Molecules Modulating Human Delta Globin Gene Expression via a Model of Transgenic Foetal Liver Cells: Implications for Beta-Hemoglobinopathy Therapeutics

Beta-hemoglobinopathies such as beta-thalassemia and sickle cell disease are severe genetic blood disorders affecting the beta globin chain of haemoglobin A (α2β2). Activation of delta globin, the non-alpha globin of HbA2 (α2δ2), could represent a possible approach to improve the clinical severity of these pathologies. Notably, the therapeutic potential of delta globin has been demonstrated in previous studies using a mouse model of beta-thalassemia and sickle cell disease. The present study evaluated <i>delta globin</i> gene activation by small molecules in erythroid cells isolated from transgenic murine foetal liver. A screening of 119 molecules, selected for their potential in drug repurposing, was performed without prior selection based on specific pathways of interest. Three candidates-Nexturastat, Stattic and Palbociclib-were found to have high efficacy on <i>delta globin</i> expression. Palbociclib also proved effective in increasing <i>gamma globin</i> expression. All of these compounds have pharmacokinetic profiles that are beneficial for clinical application, providing potential inducer agents of HbA2 that could have therapeutic effects in the treatment of beta-hemoglobinopathies.