Oral administration of the LSD1 inhibitor ORY-3001 increases fetal hemoglobin in sickle cell mice and baboons
Oral administration of the LSD1 inhibitor ORY-3001 increases fetal hemoglobin in sickle cell mice and baboons
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DOI：
10.1016/j.exphem.2018.08.003
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发表时间：
2018-11-01
影响因子：
2.6
通讯作者：
Lavelle, Donald
中科院分区：
文献类型：
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作者：
Rivers, Angela;Vaitkus, Kestis;Lavelle, Donald
胎儿血红蛋白（HbF）水平升高可减轻镰状细胞病（SCD）患者症状的严重程度并延长其寿命。需要更有效的策略来增加HbF，因为目前的标准治疗，羟基脲，在很大一部分患者中无效。预计全球数百万患者的治疗最好通过增加HbF的口服药物治疗来完成。LSD 1是辅阻遏物复合物的一个组成部分，其抑制γ-珠蛋白基因表达，并且是HbF再激活的治疗靶点。我们已经证明，皮下注射RN-1（一种药理学LSD 1抑制剂）可增加SCD小鼠和狒狒中的γ-珠蛋白表达，SCD小鼠和狒狒被广泛认为是测试HbF诱导药物活性的最佳动物模型。本研究的目的是测试口服新的LSD 1抑制剂ORY-3001的效果。向SCD小鼠（n = 3组）口服给予ORY-3001增加了γ-珠蛋白表达、含胎儿血红蛋白（HbF）的（F）细胞和F网织红细胞（网织红细胞）。在用ORY-3001处理的正常狒狒（n = 7个实验）中，观察到增加的纤维蛋白、γ-珠蛋白链合成和γ-珠蛋白mRNA。在贫血狒狒（n = 2）中的实验表明，ORY-3001增加了（PA 8695，给药前= 24%，给药后= 66.8%; PA 8698：给药前= 13%，给药后= 93.6%），γ-珠蛋白链合成（PA 8695：给药前= 0.07 γ/γ + β，给药后= 0.20 γ/γ + β; PA 8698：给药前= 0.02 γ/γ + β，给药后= 0.44 γ/γ +13）和γ-珠蛋白mRNA（PA 8695：给药前= 0.06 γ/γ + β，给药后= 0.18 γ + β; PA 8698：给药前= 0.03 γ/γ + β，给药后= 0.33 γ/γ + β）。我们得出结论，口服ORY-3001增加了狒狒和SCD小鼠中的纤维蛋白、γ-珠蛋白链合成和γ-珠蛋白mRNA，支持进一步努力开发这种用于SCD治疗的药物。(C)2018由Elsevier Inc.出版代表ISEH血液学和干细胞学会。
Increased levels of fetal hemoglobin (HbF) lessen the severity of symptoms and increase the life span of patients with sickle cell disease (SCD). More effective strategies to increase HbF are needed because the current standard of care, hydroxyurea, is not effective in a significant proportion of patients. Treatment of the millions of patients projected worldwide would best be accomplished with an orally administered drug therapy that increased HbF. LSD1 is a component of corepressor complexes that repress gamma-globin gene expression and are a therapeutic target for HbF reactivation. We have shown that subcutaneous administration of RN-1, a pharmacological LSD1 inhibitor, increased gamma-globin expression in SCD mice and baboons, which are widely acknowledged as the best animal model in which to test the activity of HbF-inducing drugs. The objective of this investigation was to test the effect of oral administration of a new LSD1 inhibitor, ORY-3001. Oral administration of ORY-3001 to SCD mice (n = 3 groups) increased gamma-globin expression, Fetal Hemoglobin (HbF)-containing (F) cells, and F reticulocytes (retics). In normal baboons (n = 7 experiments) treated with ORY-3001, increased F retics, gamma-globin chain synthesis, and gamma-globin mRNA were observed. Experiments in anemic baboons (n = 2) showed that ORY-3001 increased F retics (PA8695, predose = 24%, postdose = 66.8%; PA8698: predose = 13%, post dose = 93.6%), gamma-globin chain synthesis (PA8695: predose = 0.07 gamma/gamma+beta, postdose = 0.20 gamma/gamma+beta; PA8698: predose = 0.02 gamma/gamma+beta, postdose = 0.44 gamma/gamma+13), and gamma-globin mRNA (PA8695: predose = 0.06 gamma/gamma+beta, postdose = 0.18 yly+beta; PA8698: predose = 0.03 gamma/gamma+beta, postdose = 0.33 gamma/gamma+fi). We conclude that oral administration of ORY-3001 increases F retics, y-globin chain synthesis, and y-globin mRNA in baboons and SCD mice, supporting further efforts toward the development of this drug for SCD therapy. (C) 2018 Published by Elsevier Inc. on behalf of ISEH Society for Hematology and Stem Cells.