Conjugate prodrug AN-233 induces fetal hemoglobin expression in sickle erythroid progenitors and β-YAC transgenic mice

Aluya R. Oseghale, Xingguo Zhu, Biaoru Li, Kenneth R. Peterson, Abraham Nudelman, Ada Rephaeli, Hongyan Xu, Betty S. Pace

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Pharmacologic induction of fetal hemoglobin (HbF) is an effective strategy for treating sickle cell disease (SCD) by ameliorating disease severity. Hydroxyurea is the only FDA-approved agent that induces HbF, but significant non-responders and requirement for frequent monitoring of blood counts for drug toxicity limit clinical usefulness. Therefore, we investigated a novel prodrug conjugate of butyric acid (BA) and δ-aminolevulinate (ALA) as a potential HbF inducing agent, using erythroid precursors and a preclinical β-YAC mouse model. We observed significantly increased γ-globin gene transcription and HbF expression mediated by AN-233 in K562 cells. Moreover, AN-233 stimulated mild heme biosynthesis and inhibited expression of heme-regulated eIF2α kinase involved in silencing γ-globin expression. Studies using primary erythroid precursors generated from sickle peripheral blood mononuclear cells verified the ability of AN-233 to induce HbF, increase histone H3 and H4 acetylation levels at the γ-globin promoter and reduce erythroid precursor sickling by 50%. Subsequent drug treatment of β-YAC transgenic mice confirmed HbF induction in vivo by AN-233 through an increase in the percentage of HbF positive red blood cells and HbF levels measured by flow cytometry. These data support the potential development of AN-233 for the treatment of SCD.

Original languageEnglish (US)
Article number102345
JournalBlood Cells, Molecules, and Diseases
Volume79
DOIs
StatePublished - Nov 2019

Keywords

  • AN-233
  • Butyric acid
  • Fetal hemoglobin
  • β-YAC mice
  • δ-Aminolevulinate

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Hematology
  • Cell Biology

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