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

Autor: Oseghale AR; Vascular Biology Center, Augusta University, Augusta, GA, USA., Zhu X; Department of Pediatrics, Augusta University, Augusta, GA, USA., Li B; Department of Pediatrics, Augusta University, Augusta, GA, USA., Peterson KR; Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS, USA., Nudelman A; Chemistry Department, Bar Ilan University, Ramat Gan, Israel., Rephaeli A; Felsenstein Medical Research Center, Sackler Medical School, Tel Aviv University, Petach Tikva, Israel., Xu H; Department of Population Health Sciences, Augusta University, Augusta, GA, USA., Pace BS; Vascular Biology Center, Augusta University, Augusta, GA, USA; Department of Pediatrics, Augusta University, Augusta, GA, USA; Department of Biochemistry and Molecular Biology, Augusta University, Augusta, GA, USA. Electronic address: bpace@augusta.edu.
Jazyk: angličtina
Zdroj: Blood cells, molecules & diseases [Blood Cells Mol Dis] 2019 Nov; Vol. 79, pp. 102345. Date of Electronic Publication: 2019 Jul 09.
DOI: 10.1016/j.bcmd.2019.102345
Abstrakt: 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.
(Copyright © 2019. Published by Elsevier Inc.)
Databáze: MEDLINE
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