Novel Inducers of Fetal Globin Identified through High Throughput Screening (HTS) Are Active In Vivo in Anemic Baboons and Transgenic Mice
| Autor: | Roman F. Wolf, Douglas V. Faller, Levi Makala, Jose Sangerman, Emily White, Betty S. Pace, Gary L. White, Mehdi Nouraie, Ling Shen, Michael S. Boosalis, Biaoru Li, Susan P. Perrine, Yan Dai |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Genetically modified mouse
Transcriptional Activation Transgene High-throughput screening Drug Evaluation Preclinical lcsh:Medicine Mice Transgenic Pharmacology Biology Benserazide Mice In vivo Fetal hemoglobin medicine Animals gamma-Globins Globin RNA Messenger lcsh:Science Fetal Hemoglobin Erythroid Precursor Cells Reporter gene Multidisciplinary lcsh:R Anemia Loratadine Molecular biology 3. Good health High-Throughput Screening Assays lcsh:Q medicine.drug Research Article Papio |
| Zdroj: | PLoS ONE PLoS ONE, Vol 10, Iss 12, p e0144660 (2015) |
| ISSN: | 1932-6203 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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