HbF inducer

Rationale
Inducers of fetal haemoglobin (HbF), or HbF inducers, are substances that reactivate or enhance γ-globin gene expression in adults. Several observations lead to the conclusion that production of HbF can functionally compensate for the absence of β-globin chain production,    including the intriguing finding that a group of genetic  mutations, known as hereditary persistence of fetal haemoglobin (HPFH), are associated with high levels of  HbF in adults resulting in a mild phenotype. Most of the HPFH patients homozygous for β-thalassaemia mutations do not need blood transfusion. Therefore, there has been considerable interest in recent years in finding ways of increasing production of HbF by reactivating the γ-globin genes. In Table 1 a list of HbF inducers is reported. Unfortunately, several of these drugs have low efficacy and specificity, and some of them are potentially carcinogenic. Therefore, there is an urgent need to optimise experimental model systems for large-scale screening of HbF inducers and to identify new types of agents that can induce  HbF production with greater efficiency and lower toxicity.

Table 1. ''*Modified from Gambari and Fibach. ''

Clinical Trials
Clinical trials aimed at increasing HbF synthesis in β-thalassemia and SCA patients have included administration of cell-cycle-specific agents, hematopoietic growth factors and short-chain fatty acids, all of which stimulate γ-globin synthesis by different mechanisms. Compounds such as 5-azacytidine, hydroxyurea (HU) and butyrate analogues have been used most frequently (Table 2). As a representative example, Yavarian et al. reported the treatment with HU in 133 patients diagnosed with transfusion-dependent β-thalassaemia. These patients were classified into three categories of response: a good response (61%) in patients who shifted from monthly blood transfusion dependency to a stable transfusion-free condition; a moderate response (23%) in patients who remained transfusion dependent but at longer intervals (6 months or more), and non-response in patients who, after 1 year of treatment, remained at the same level of transfusion dependency. As far as demethylating agents tested in Phase I/II studies, decitabine, used at DNA hypomethylating, but non-cytotoxic doses, was well tolerated and effective in increasing HbF and total Hb levels in patients affected by haemoglobin disorders. Therapy with butyrates has been also reported. When all these clinical data are considered together, it appears that HbF inducers are clinically beneficial for patients affected by β-thalassaemia and sickle cell disease (SCD).

Table 2. aDosages were 5–20 mg kg−1 day−1; bOnly patients needing transfusions are included; cTransfusion-free patients.