The natural history of severe
hemoglobinopathies like
sickle cell disease (SCD) is rather variable, depending on the circumstances, but the main influence on such variability is the level of
fetal hemoglobin (HbF) in the patient's red cells. It is well known that a significant HbF level is associated with a milder course of disease and fewer complications. Therefore, attempts have been made to reactivate using various means the HbF production, which is normally switched off perinatally. A pharmacological approach has been attempted since the 1980s, ranging from drugs like
5-azacytidine and its derivative,
decitabine, to a series of compounds like
hydroxyurea and a number of
histone deacetylase inhibitors like
butyrate, which seem to act as epigenetic modifiers. Many other disparate agents have been tried with mixed results, but
hydroxyurea remains the most effective compound so far available. Combinations of different compounds have also been tried with some success. Established treatments like bone marrow or cord blood
transplantation are so far the only real cure for a limited number of patients with severe
hemoglobinopathies. Improved
chemotherapy regimens of milder toxicity than those employed in the past have made it possible recently to obtain a stable, mixed donor-recipient chimerism, with reversal of the SCD phenotype. However, great effort is directed to cell engineering, searching for an effective gene vector by which a desired gene can be transferred into new classes of vectors for autologous hemopoietic stem cells. Recent studies are also aiming at targeted insertion of the therapeutic gene into hemopoietic cells, which can also be "induced" human stem cells, obtained from somatic dedifferentiated cells. Attention in this area must be paid to the possibility of undesired effects, like the emergence of potentially oncogenic cell populations. Finally, an update is presented on improved HbF determination methods, because common international standards are becoming mandatory.