Conjugate prodrug AN-233 induces fetal hemoglobin expression in sickle erythroid progenitors and ß-YAC transgenic mice.
Blood Cells Mol Dis
; 79: 102345, 2019 11.
Article
in En
| MEDLINE
| ID: mdl-31351219
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 ß-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 ß-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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Fetal Hemoglobin
/
Prodrugs
/
Erythroid Precursor Cells
/
Anemia, Sickle Cell
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Levulinic Acids
Limits:
Animals
/
Humans
Language:
En
Journal:
Blood Cells Mol Dis
Journal subject:
HEMATOLOGIA
Year:
2019
Type:
Article
Affiliation country:
United States