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Induction of fetal globin in beta-thalassemia: Cellular obstacles and molecular progress - PubMed

  • ️Thu Dec 01 2005

Clinical Trial

Induction of fetal globin in beta-thalassemia: Cellular obstacles and molecular progress

Susan P Perrine et al. Ann N Y Acad Sci. 2005.

Abstract

Accelerated apoptosis of erythroid progenitors in beta-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 beta+-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 beta 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 beta-thalassemia. Both approaches now offer excellent potential for tolerable, definitive treatment of beta-thalassemia.

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Figures

Figure 1
Figure 1

(A) Pharmacokinetic profiles of a novel SCFAD, RB16, administered at single oral doses of 10 mg/kg (open squares) and 20 mg/kg (closed symbols) in a baboon. The compound persisted in the plasma above the target concentration for more than 24 h following single oral doses. This target concentration induces fetal globin expression in erythroid cultures established from patients with β+-thalassemia, as shown by the dotted line. (B) Fetal globin mRNA before and during administration of RB16 in a nonanemic baboon. The test compound was administered once/day, 5 days/week during days 1–28 and for 4 days/week for another 2 weeks, as shown by the bars above the graph. A four- to sixfold induction of fetal globin mRNA above baseline was observed, as shown. The period of administration of the study compound is designated by the lines above the graph.

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