Induction of Fetal Globin in β‐Thalassemia: Cellular Obstacles and Molecular Progress

Abstract

Accelerated apoptosis of erythroid progenitors in β-thalassemia is a significant barrier to definitive therapy because the beneficial effects of fetal globin-inducing agents on globin chain balance may not be inducible in cells in which programmed cell death is established early. Accordingly, our objectives have been to identify methods to decrease cellular apoptosis and to identify orally tolerable fetal globin gene inducers. A pilot clinical trial was conducted to determine whether combined use of a fetal globin gene inducer (butyrate) and rhu-erythropoietin (EPO), the hematopoietic growth factor that prolongs erythroid cell survival and stimulates erythroid proliferation, would produce additive hematologic responses in any thalassemia subjects. Butyrate and EPO were administered in 10 patients. Novel fetal globin gene inducers that also stimulate erythroid proliferation were evaluated for pharmacokinetic profiles. Patients with β + -thalassemia had relatively low levels of endogenous EPO (<145 mU/mL) and had additive responses to administered EPO and butyrate. Patients with at least one β 0 -globin mutation had higher baseline HbF levels (>60%) and EPO levels (>160 mU/mL), and three-fourths of these subjects responded to the fetal globin gene inducer alone. A few select fetal globin-inducing short-chain fatty acid derivatives that stimulated cell proliferation also had favorable pharmacokinetics. These studies identify a significant subset of thalassemia patients who appear to require exogenous EPO to respond optimally to any HbF inducer, as well as new therapeutic candidates that act on both cellular and molecular pathologies of β-thalassemia. Both approaches now offer excellent potential for tolerable, definitive treatment of β-thalassemia.

Histone Deacetylase 9 Activates γ-Globin Gene Expression in Primary Erythroid Cells

“…In other cell types, these drugs also alter Class I and Class II HDAC proteins that are dependent on zinc ion for enzymatic activity (32,33). However, in erythroid cells, the magnitude of HDAC inhibition does not directly correlate with the magnitude of ␥-globin induction by these compounds (13,34), suggesting that HDAC subtypes or site-specific acetylation may be an important mechanism involved in ␥-globin gene activation.…”

Neither DNA hypomethylation nor changes in the kinetics of erythroid differentiation explain 5-azacytidine's ability to induce human fetal hemoglobin

“…28 Several cell-signaling pathways have been implicated in fetal globin gene regulation in a variety of experimental systems, including those involving nitric oxide, 29 p38 MAPK, 30 STAT3␤, 31 cGMP, 29,32 cAMP, 33 and cytokine signaling. 34,35 It is possible that 5-Aza and decitabine, as well as other inducers of fetal Hb, act through these or other pathways.…”

Short-term Toxicity Study of ST-20 (NSC-741804) by Oral Gavage in Sprague-Dawley Rats

“…Sodium phenylbutyrate and arginine butyrate increase total hemoglobin in beta thalassemia patients (Perrine et al 1993;Collins et al 1995;Ikuta et al 1998;Atweh, Sutton, and Nassif 1999;Perrine et al 2005). However, the use of these agents has been limited by rapid metabolism necessitating intravenous administration of excessively large doses, and by antiproliferative effects on erythroid cell growth, requiring intermittent use (Atweh, Sutton, and Nassif 1999;Perrine et al 2005). In an effort to identify an orally active SCFAD with more favorable pharmacokinetic (PK) features, ST-20 was discovered after extensive screening of a panel of SCFADs and a chemical library of 13,000 compounds using computational modeling.…”