New therapies for the haemoglobinopathies

Re-activation of the fetal globin genes is the most realistic approach to correct the deranged pathophysiology of the haemoglobinopathies because the presence of gamma-chains can neutralize the toxic effects of the unbound alpha-globin chains in the beta-thalassaemias and inhibit the polymerization of Hb S in the sickle cell syndromes. Re-induction of fetal haemoglobin synthesis can be brought about either by direct activation of the respective promoter genes and possibly other positively acting elements, or by recruitment into proliferation and differentiation of a population of erythroid precursors which retain the gamma-chain synthesis programme but remain dormant in the bone marrow of the adult unless called up in cases of acute erythroid expansion. Examples of the first group include the butyric acid and derivatives and 5' azacytidine. The second group comprises erythropoietin and a series of cytostatics, with hydroxyurea as the main representative. The activity of most of the above agents has already been studied in cell cultures and animals and confirmed in several patients, both at the haematological and biochemical level as well as through their frank clinical improvement. However, application of these drugs at large is not yet justified because a series of questions concerning their long-term efficacy, the correct dosage and timing, their tolerance and toxicity, and the potential long-term dangers, including mutagenicity are still unresolved.