The treatments available for thalassemia are rapidly evolving, with major advances made in gene therapy and the modulation of erythropoiesis. The latter includes the therapeutic potential of hepcidin tuning. In thalassemia, hepcidin is significantly depressed, and any rise in hepcidin function has a positive effect on both iron metabolism and erythropoiesis.
Synthetic hepcidin and hepcidin mimetics have been developed to the stage of clinical trials. However, they have failed to produce an acceptable efficacy/safety profile. It seems difficult to avoid iron over-restricted erythropoiesis when directly using hepcidin as a drug. Indirect approaches, each one with their advantages and disadvantages, are many and in full development.
The ideal approach is to target erythroferrone, the main inhibitor of hepcidin expression, the plasma concentrations of which are greatly increased in iron-loading anemias. Potential means of improving hepcidin function in thalassemia also include acting on TMPRSS6, TfR1, TfR2 or ferroportin, the target of hepcidin. Only having a better understanding of the crosslinks between iron metabolism and erythropoiesis will elucidate the best single option. In the meantime, many potential combinations are currently being explored in preclinical studies.
Any long-term clinical study on this approach should include the wide monitoring of functions, as the effects of hepcidin and its modulators are not limited to iron metabolism and erythropoiesis. It is likely that some of the aspects of hepcidin tuning described briefly in this review will play a role in the future treatment of thalassemia.Read Publication