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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.
Highlights
The β-thalassemias and sickle cell disease (SCD), genetic disorders affecting the β-chain of adult hemoglobin A, are serious anemias and comprise a growing global health burden [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24]
High activity was found with Idarubicin, as previously reported[19], which validated the high throughput screening (HTS) system
Additional therapeutics should beneficial for treatment of the diverse global hemoglobinopathy population[4,5,6]
Summary
The β-thalassemias and sickle cell disease (SCD), genetic disorders affecting the β-chain of adult hemoglobin A, are serious anemias and comprise a growing global health burden [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24]. High-Throughput Screen Generated Potent Fetal Globin Inducers is a commercial organization, which provided partial funding for this work (through NIH grants), and did not play a role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript and only provided financial support in the form of authors' salaries and/or research materials. The funder provided support in the form of partial salaries for authors [SPP, DVF] and experimental expenses, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the “author contributions’ section”
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