The first clinical trials aimed at reversing HbF silencing in patients with sickle cell anemia and β-thalassemia targeted DNA methylation with 5-azacytidine.43, 44 and 45 Although subsequent trials with cytotoxic agents raised questions as to the exact mechanism of 5-azacytidine–induced HbF expression,13 a Smad inhibitor number of preclinical studies support a major role for DNA hypomethylation.51, 52, 53, 55 and 56 As noted previously, concerns about adverse effects of hypomethylating agents with
known cytotoxicity have limited the widespread use of 5-azacytidine and decitabine in the clinic. The use of HDAC inhibitors represents the other major example of clinical trials aimed at targeting epigenetic silencing of HbF expression in patients Ganetespib cell line with β-globin gene disorders.76, 77 and 97 Recent trials with oral butyrate derivatives have shown activity in patients with β-thalassemia. One such agent sodium 2,2-dimethyl butyrate was shown to be tolerated in phase I/II trial.98 Although butyrate and derivative compounds have demonstrated effectiveness in some patients, the effects are variable. The nature of this variability remains unknown and could involve differences in metabolism of various HDAC inhibitors or genetic heterogeneity in acetylated protein targets or downstream regulatory factors in different patients. On
the basis of the preclinical studies described previously, a number of epigenetic modulators are either in early phase learn more clinical trial testing or such trials are being planned. Among these are inhibitors of the histone lysine demethylase, LSD1,86 and 88 the histone arginine methylase, PRMT5,83 and selective HDAC1 and HDAC2 inhibitors.78
The development of more selective HDAC inhibitors may increase their effectiveness, whereas decreasing the unwanted adverse effects of these agents. In the face of a large number of epigenetic targets for inducing HbF expression in patients with β-thalassemia and sickle cell anemia, consideration of several factors should guide the further development of targeting strategies. The same considerations also apply to therapeutic targeting of transcription factors such as BCL11A and KLF1. The first is selection of the most informative preclinical model systems to identify promising agents. Human β-globin locus–bearing transgenic mice have provided a valuable model to identify important epigenetic and transcription factor silencers of embryonic/fetal β-globin gene expression. However, as noted previously, because mice only have embryonic and adult β-globin expression, this model may either underestimate or overestimate the effect that a given epigenetic or genetic fetal globin gene silencer will have in humans. Cultured human primary erythroid cells derived from CD34+ progenitors also provide a valuable model for identifying epigenetic targets for inducing HbF expression.