Novel inducers of fetal globin identified through high throughput screening (HTS) are active in vivo in anemic baboons and transgenic mice

Michael S. Boosalis, Jose I. Sangerman, Gary L. White, Roman F. Wolf, Ling Shen, Yan Dai, Emily White, Levi H. Makala, Biaoru Li, Betty S. Pace, Mehdi Nouraie, Douglas V. Faller, Susan P. Perrine

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

High-level fetal (γ) globin expression ameliorates clinical severity of the beta (β) hemoglobinopathies, and safe, orally-bioavailable γ-globin inducing agents would benefit many patients. We adapted a LCR-γ-globin promoter-GFP reporter assay to a high-throughput robotic system to evaluate five diverse chemical libraries for this activity. Multiple structurally- And functionally-diverse compounds were identified which activate the γ-globin gene promoter at nanomolar concentrations, including some therapeutics approved for other conditions. Three candidates with established safety profiles were further evaluated in erythroid progenitors, anemic baboons and transgenic mice, with significant induction of γ-globin expression observed in vivo. A lead candidate, Benserazide, emerged which demonstrated > 20-fold induction of γ-globin mRNA expression in anemic baboons and increased F-cell proportions by 3.5-fold in transgenic mice. Benserazide has been used chronically to inhibit amino acid decarboxylase to enhance plasma levels of L-dopa. These studies confirm the utility of high-throughput screening and identify previously unrecognized fetal globin inducing candidates which can be developed expediently for treatment of hemoglobinopathies.

Original languageEnglish (US)
Article number0144660
JournalPloS one
Volume10
Issue number12
DOIs
StatePublished - Dec 1 2015

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Boosalis, M. S., Sangerman, J. I., White, G. L., Wolf, R. F., Shen, L., Dai, Y., White, E., Makala, L. H., Li, B., Pace, B. S., Nouraie, M., Faller, D. V., & Perrine, S. P. (2015). Novel inducers of fetal globin identified through high throughput screening (HTS) are active in vivo in anemic baboons and transgenic mice. PloS one, 10(12), [0144660]. https://doi.org/10.1371/journal.pone.0144660