Novel Inducers of Fetal Globin Identified through High Throughput Screening (HTS) Are Active In Vivo in Anemic Baboons and Transgenic Mice

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dc.contributor.authorMichael S. Boosalis
dc.contributor.authorJose I. Sangerman
dc.contributor.authorGary L. White
dc.contributor.authorRoman F. Wolf
dc.contributor.authorLing Shen
dc.contributor.authorYan Dai
dc.contributor.authorEmily White
dc.contributor.authorLevi H. Makala
dc.contributor.authorBiaoru Li
dc.contributor.authorBetty S. Pace
dc.contributor.authorMehdi Nouraie
dc.contributor.authorDouglas V. Faller
dc.contributor.authorSusan P. Perrine
dc.date.accessioned2017-03-05T22:55:24Z
dc.date.available2017-03-05T22:55:24Z
dc.date.issued2015-12-29
dc.descriptionWe thank Sarah Haigh, Ada Kane, Nicole Reuter, David Carey, and Marilyn Perry Carey for dedicated and expert technical assistance and Cloret Carl for assistance with preparation of the manuscript.This work was supported by grants from the National Institutes of Health, R01 DK-52962, (SPP, Boston University), R41 HL-105816 (SPP, Phoenicia BioSciences), and R42 HL-110727 (Phoenicia BioSciences), 2 P40 ODO010988-16 (GLW, University of Oklahoma) and UL1-TR000157 (RFW, University of Oklahoma). SMN was supported by P50 HL-118006. The funders had no role in study design, data collection or analysis, decision to publish, or preparation of the manuscript.en_US
dc.descriptionen_US
dc.description.abstractHigh-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.en_US
dc.description.peerreviewYesen_US
dc.description.peerreviewnoteshttp://www.plosone.org/static/editorial#peeren_US
dc.identifier.citationBoosalis MS, Sangerman JI, White GL, Wolf RF, Shen L, Dai Y, et al. (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): e0144660. doi:10.1371/journal.pone.0144660en_US
dc.identifier.doi10.1371/journal.pone.0144660en_US
dc.identifier.urihttp://hdl.handle.net/11244/49283
dc.language.isoen_USen_US
dc.publisherPLos One
dc.relation.ispartofseriesPLoS ONE 10(12): e0144660
dc.relation.urihttp://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0144660
dc.rightsAttribution 3.0 United States
dc.rights.requestablefalseen_US
dc.rights.urihttp://creativecommons.org/licenses/by/3.0/us/
dc.subjectGlobins,Baboons,Hemoglobin,Mouse models,Drug administration,Drug therapy,High throughput screening,Hemoglobinopathiesen_US
dc.titleNovel Inducers of Fetal Globin Identified through High Throughput Screening (HTS) Are Active In Vivo in Anemic Baboons and Transgenic Miceen_US
dc.typeResearch Articleen_US

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