title: Novel Inducers of Fetal Globin Identified through High Throughput Screening (HTS) Are Active In Vivo in Anemic Baboons and Transgenic Mice.
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.
authors.affiliation: Cancer Center and Hemoglobinopathy Thalassemia Research Unit, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Boosalis
authors.affiliation: Cancer Center and Hemoglobinopathy Thalassemia Research Unit, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Jose I
authors.initials: JI
authors.lastname: Sangerman
authors.affiliation: Department of Comparative Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States of America.
authors.forename: Gary L
authors.initials: GL
authors.lastname: White
authors.affiliation: Department of Comparative Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States of America.
authors.forename: Roman F
authors.initials: RF
authors.lastname: Wolf
authors.affiliation: Cancer Center and Hemoglobinopathy Thalassemia Research Unit, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Ling
authors.initials: L
authors.lastname: Shen
authors.affiliation: Cancer Center and Hemoglobinopathy Thalassemia Research Unit, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Yan
authors.initials: Y
authors.lastname: Dai
authors.affiliation: Department of Comparative Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States of America.
authors.forename: Emily
authors.initials: E
authors.lastname: White
authors.affiliation: Department of Pediatrics, Georgia Regents University, Augusta, Georgia, United States of America.
authors.forename: Levi H
authors.initials: LH
authors.lastname: Makala
authors.affiliation: Department of Pediatrics, Georgia Regents University, Augusta, Georgia, United States of America.
authors.forename: Biaoru
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Pediatrics, Georgia Regents University, Augusta, Georgia, United States of America.
authors.forename: Betty S
authors.initials: BS
authors.lastname: Pace
authors.affiliation: Department of Medicine, Center for Sickle Cell Disease, Howard University, Washington, DC, United States of America.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Nouraie
authors.affiliation: Cancer Center and Hemoglobinopathy Thalassemia Research Unit, Boston University School of Medicine, Boston, Massachusetts, United States of America.|Phoenicia BioSciences, Weston, Massachusetts, United States of America.
authors.forename: Douglas V
authors.initials: DV
authors.lastname: Faller
authors.affiliation: Cancer Center and Hemoglobinopathy Thalassemia Research Unit, Boston University School of Medicine, Boston, Massachusetts, United States of America.|Phoenicia BioSciences, Weston, Massachusetts, United States of America.
authors.forename: Susan P
authors.initials: SP
authors.lastname: Perrine
mesh_terms: D000740:Anemia / Q000235:genetics*; D000818:Animals; D001545:Benserazide / Q000009:adverse effects / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D015672:Erythroid Precursor Cells / Q000187:drug effects; D005319:Fetal Hemoglobin / Q000235:genetics*; D057166:High-Throughput Screening Assays; D017336:Loratadine / Q000009:adverse effects / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D010215:Papio; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects*; D055545:gamma-Globins / Q000235:genetics*
chemical_list: D012333:RNA, Messenger; D055545:gamma-Globins; D001545:Benserazide; D017336:Loratadine; D005319:Fetal Hemoglobin; C121345:desloratadine