The LSD1 inhibitor RN-1 recapitulates the fetal pattern of hemoglobin synthesis in baboons (P. anubis)
The LSD1 inhibitor RN-1 recapitulates the fetal pattern of hemoglobin synthesis in baboons (P. anubis)
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DOI：
10.3324/haematol.2015.140749
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发表时间：
2016-06-01
期刊：
影响因子：
10.1
通讯作者：
Lavelle, Donald
中科院分区：
文献类型：
--
作者：
Rivers, Angela;Vaitkus, Kestis;Lavelle, Donald
胎儿血红蛋白水平的增加可以减轻症状的严重程度，并延长镰状细胞病患者的寿命。羟基脲是目前唯一批准用于治疗镰状细胞病的药物，对大部分患者无效，因此长期以来一直在寻找增加胎儿血红蛋白水平的新药理学药物。最近鉴定LSD-1作为γ-珠蛋白表达的阻遏物的研究导致实验证明LSD-1抑制剂RN-1增加镰状细胞小鼠模型中的β-珠蛋白表达。由于β-珠蛋白基因的排列和发育阶段特异性表达模式在人类和狒狒之间高度保守，狒狒模型仍然是人类胎儿血红蛋白诱导剂活性的最佳预测因子。在这份报告中，我们证明RN-1在贫血和非贫血狒狒中均可增加γ-珠蛋白合成、胎儿血红蛋白和F细胞至高水平，其活性与地西他滨相当，已知最有效的胎儿血红蛋白诱导剂RN-1不仅能恢复高水平的胎儿血红蛋白，而且还能使单个的5' I γ-和3' V γ-珠蛋白链以胎儿发育的特征性比例合成。胎儿血红蛋白的增加与γ-球蛋白基因上乙酰化组蛋白H3、H3 K4 Me 2、H3 K4 Me 3和RNA聚合酶II水平的增加以及γ-球蛋白启动子DNA甲基化的减少有关。RN-1可能会诱导镰状细胞病患者出现临床相关的胎儿血红蛋白水平，尽管可能需要谨慎滴定剂量以最大限度地减少骨髓毒性。
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 gamma-globin expression led to experiments demonstrating that the LSD-1 inhibitor RN-1 increased beta-globin expression in the sickle cell mouse model. Because the arrangement and developmental stage-specific expression pattern of the beta-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 gamma-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' I gamma- and 3' V gamma-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 gamma-globin gene, and diminished gamma-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.