RN-1, a potent and selective lysine-specific demethylase 1 inhibitor, increases γ-globin expression, F reticulocytes, and F cells in a sickle cell disease mouse model.
RN-1, a potent and selective lysine-specific demethylase 1 inhibitor, increases γ-globin expression, F reticulocytes, and F cells in a sickle cell disease mouse model.
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DOI：
10.1016/j.exphem.2015.04.005
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发表时间：
2015-07
影响因子：
2.6
通讯作者：
Lavelle D
中科院分区：
文献类型：
--
作者：
Rivers A;Vaitkus K;Ruiz MA;Ibanez V;Jagadeeswaran R;Kouznetsova T;DeSimone J;Lavelle D
胎儿血红蛋白水平升高与镰状细胞病（SCD）患者症状减轻和寿命延长相关。目前批准用于SCD的唯一药物羟基脲对大部分患者无效，因此迫切需要新的药物。最近的研究表明，赖氨酸脱甲基酶-1（LSD 1），一种从组蛋白H3的赖氨酸4残基上去除单甲基和二甲基残基的酶，是γ-珠蛋白基因表达的阻遏物。在这份报告中，我们比较了反苯环丙胺（TCP）和一种更有效的TCP衍生物RN-1在培养的狒狒红系祖细胞和SCD小鼠模型中增加γ-珠蛋白表达的能力。我们的研究结果表明，RN-1诱导SCD小鼠中F细胞和γ-珠蛋白mRNA的能力与地西他滨（已知最强的HbF诱导药物）相似，并且大于TCP或羟基脲。我们的结论是RN-1和其他LSD 1抑制剂可能是一种有前途的新的γ-珠蛋白诱导剂，用于治疗镰状细胞病，值得在其他临床前模型，如非人灵长类动物中进一步研究。
Increased levels of fetal hemoglobin are associated with decreased symptoms and increased life span in patients with sickle cell disease (SCD). Hydroxyurea, the only drug currently approved for SCD, is not effective in a large fraction of patients and therefore new agents are urgently needed. Recently it was shown that Lysine Demethylase-1 (LSD1), an enzyme that removes monomethyl and dimethyl residues from the lysine 4 residue of histone H3, is a repressor of γ-globin gene expression. In this report we have compared the ability of tranylcypromine (TCP) and a more potent TCP derivative, RN-1, to increase γ-globin expression in cultured baboon erythroid progenitor cells and in the SCD mouse model. Our results show that the ability of RN-1 to induce F-cells and γ-globin mRNA in SCD mice was similar to decitabine, the most powerful HbF-inducing drug known, and greater than either TCP or hydroxyurea. We conclude that RN-1 and other LSD1 inhibitors may be a promising new γ-globin inducing agent for the treatment of sickle cell disease that warrant further studies in other pre-clinical models such as non-human primates.
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影响因子：
2.9
作者：
Ofori-Acquah, SF;Green, BN;Layton, DM
通讯作者：
Layton, DM
影响因子：
64.8
作者：
SUNSHINE, HR;HOFRICHTER, J;EATON, WA
通讯作者：
EATON, WA
DOI：
10.1073/pnas.1303976110
发表时间：
2013-04-16
影响因子：
11.1
作者：
Xu, Jian;Bauer, Daniel E.;Orkin, Stuart H.
通讯作者：
Orkin, Stuart H.
影响因子：
158.5
作者：
PLATT, OS;BRAMBILLA, DJ;KLUG, PP
通讯作者：
KLUG, PP
影响因子：
7.7
作者：
Kerenyi MA;Shao Z;Hsu YJ;Guo G;Luc S;O'Brien K;Fujiwara Y;Peng C;Nguyen M;Orkin SH
通讯作者：
Orkin SH