title: The LSD1 inhibitor RN-1 recapitulates the fetal pattern of hemoglobin synthesis in baboons (P. anubis).
abstract: Increased fetal hemoglobin levels lessen the severity of symptoms and increase the lifespan of patients with sickle cell disease. Hydroxyurea, the only drug currently approved for the treatment of sickle cell disease, is not effective in a large proportion of patients and therefore new pharmacological agents that increase fetal hemoglobin levels have long been sought. Recent studies identifying LSD-1 as a repressor of γ-globin expression led to experiments demonstrating that the LSD-1 inhibitor RN-1 increased γ-globin expression in the sickle cell mouse model. Because the arrangement and developmental stage-specific expression pattern of the β-like globin genes is highly conserved between man and baboon, the baboon model remains the best predictor of activity of fetal hemoglobin-inducing agents in man. In this report, we demonstrate that RN-1 increases γ-globin synthesis, fetal hemoglobin, and F cells to high levels in both anemic and non-anemic baboons with activity comparable to decitabine, the most potent fetal hemoglobin-inducing agent known. RN-1 not only restores high levels of fetal hemoglobin but causes the individual 5' Iγ- and 3' Vγ-globin chains to be synthesized in the ratio characteristic of fetal development. Increased fetal hemoglobin was associated with increased levels of acetylated Histone H3, H3K4Me2, H3K4Me3, and RNA polymerase II at the γ-globin gene, and diminished γ-globin promoter DNA methylation. RN-1 is likely to induce clinically relevant levels of fetal hemoglobin in patients with sickle cell disease, although careful titration of the dose may be required to minimize myelotoxicity.
authors: Department of Pediatrics, University of Illinois at Chicago, Chicago, IL, USA Jesse Brown VA Medical Center, Chicago, IL, USA.
authors: Angela
authors: A
authors: Rivers
authors: Jesse Brown VA Medical Center, Chicago, IL, USA Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
authors: Kestis
authors: K
authors: Vaitkus
authors: Jesse Brown VA Medical Center, Chicago, IL, USA Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
authors: Vinzon
authors: V
authors: Ibanez
authors: Jesse Brown VA Medical Center, Chicago, IL, USA Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
authors: Maria Armila
authors: MA
authors: Ruiz
authors: Department of Pediatrics, University of Illinois at Chicago, Chicago, IL, USA Jesse Brown VA Medical Center, Chicago, IL, USA.
authors: Ramasamy
authors: R
authors: Jagadeeswaran
authors: Department of Hematology and Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.
authors: Yogen
authors: Y
authors: Saunthararajah
authors: Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, USA.
authors: Shuaiying
authors: S
authors: Cui
authors: Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, USA.
authors: James D
authors: JD
authors: Engel
authors: Jesse Brown VA Medical Center, Chicago, IL, USA Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
authors: Joseph
authors: J
authors: DeSimone
authors: Jesse Brown VA Medical Center, Chicago, IL, USA Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA dlavelle@uic.edu.
authors: Donald
authors: D
authors: Lavelle
mesh_terms: D000740:Anemia / Q000097:blood / Q000188:drug therapy / Q000209:etiology; D000818:Animals; D001772:Blood Cell Count; D019175:DNA Methylation / Q000187:drug effects; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005319:Fetal Hemoglobin / Q000096:biosynthesis* / Q000235:genetics*; D005786:Gene Expression Regulation / Q000187:drug effects; D056466:Histone Demethylases / Q000037:antagonists & inhibitors*; D006657:Histones / Q000378:metabolism; D010215:Papio; D012156:Reticulocytes / Q000187:drug effects / Q000378:metabolism; D055545:gamma-Globins / Q000096:biosynthesis / Q000235:genetics
chemical_list: D004791:Enzyme Inhibitors; D006657:Histones; D055545:gamma-Globins; D005319:Fetal Hemoglobin; D056466:Histone Demethylases