Foetal haemoglobin inducers for reducing blood transfusion in non-transfusion-dependent beta-thalassaemias

New Synthetic Isoxazole Derivatives Acting as Potent Inducers of Fetal Hemoglobin in Erythroid Precursor Cells Isolated from β-Thalassemic Patients

“…In order to verify the possible impact of c4 in the development of therapeutic approaches for β-thalassemia, we examined the HbF inducing activity of c4 (a) in ErPCs from patients with different genotypes ( Figure 9 A) and (b) in comparison with inducers presently employed in clinical trials ( Figure 9 B). We selected hydroxyurea and rapamycin; hydroxyurea is employed in several clinical trials, such as NCT03183375 and NCT00809042 [ 38 , 39 , 40 , 41 , 42 , 43 ], while rapamycin (sirolimus) is employed in two clinical trials (NCT03877809 (A Personalized Medicine Approach for β-thalassemia Transfusion Dependent Patients: Testing sirolimus in a First Pilot Clinical Trial) and NCT04247750 (Treatment of β-thalassemia Patients with Rapamycin (Sirolimus): From Pre-clinical Research to a Clinical Trial) [ 44 ].…”

“…Currently, hydroxyurea (HU) is the only one approved drug able to induce fetal hemoglobin [ 14 , 18 , 38 , 39 , 40 , 41 ]. However, the side effects (as leukopenia and neutropenia) of the HU treatment, and the fact that it is active only in some patients, attracts limited enthusiasm for the use of this molecule [ 42 , 43 ].…”

“…However, the side effects (as leukopenia and neutropenia) of the HU treatment, and the fact that it is active only in some patients, attracts limited enthusiasm for the use of this molecule [ 42 , 43 ]. For these reasons, several research teams are trying to identify new molecules capable of inducing HbF expression with greater efficiency and lower toxicity than the HU [ 39 ].…”

“…These cells, isolated from patients with different genotypes ( Figure 3 ), represent an excellent model system for screening HbF inducers that are to be considered in pre-clinical studies for developing therapeutic protocols for β-thalassemia. For this reason, in our study, the biological effects of the isoxazole derivatives were compared with those of two well-known HbF inducers, HU and rapamycin, which are both employed in clinical trials for β-thalassemia [ 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 ].…”