Inactivation of LSD1 as a possible treatment for sickle cell disease

描述(申请人提供)：镰状细胞病(SCD)和b-地中海贫血共同构成人类最常见的遗传性疾病。目前治疗SCD的唯一方法是羟基脲(HU)治疗。在大约一半的治疗患者中，HU诱导胎儿血红蛋白(Hbf)合成的机制尚不清楚(S)，其长期效果大多尚不清楚。临床上已知，HBF诱导可以减少SCD患者的器官发病率和疼痛，并抑制镰刀状聚合物的形成，从而抑制体外红细胞的破坏。在过去的十年里，我的实验室一直在研究一种名为Dred的胎儿g-珠蛋白基因抑制物。我们最近报道了Dred的亚基组成，它至少由四个不同的表观遗传修饰物共抑制物多蛋白复合体组成。其中一种修饰酶是LSD1，这是一种单胺氧化酶，可以去除激活的染色质特征，从而导致基因抑制。我们最近测试了一种高度特异的LSD1抑制剂，称为三羟环丙胺(TC)。我们发现，在体外诱导人CD34+造血干细胞向红系细胞分化的过程中，HBF以TC剂量依赖的方式被诱导到治疗水平。我们已经为TC申请了一项新的使用专利，该专利已经获得FDA的批准，并打算在细胞和镰状细胞小鼠中测试隐蔽特性(HBF诱导)。如果这些初步试验是有成效的，我们将在未来启动对白血病和镰状细胞患者的临床试验。

DESCRIPTION (provided by applicant): Sickle cell disease (SCD) and b-thalassemia together comprise the most commonly inherited diseases in man. The only current therapy for SCD is treatment with hydroxyurea (HU). HU induces fetal hemoglobin (HbF) synthesis in about half of treated patients by as yet unknown mechanism(s), and its long term effects are largely unknown. HbF induction is known clinically to reduce organ morbidity and pain in SCD patients, and to inhibit sickle polymer formation and consequently destruction of erythrocytes in vitro. For the past decade, my lab has studied a fetal g-globin gene repressor called DRED. We recently reported the subunit composition of DRED, which is composed of at least four distinct epigenetic modifier co-repressor multiprotein complexes. One of the modifying enzymes is LSD1, a monoamine oxidase that removes activating chromatin signatures, thereby leading to gene repression. We recently tested a highly specific inhibitor for LSD1 called tranylcypromine (TC). We found that in human CD34+ hematopoietic stem cells induced to differentiate into erythroid cells in vitro, HbF was induced to therapeutic levels in a TC dosage-dependent manner. We have filed a novel use patent for TC, which is already FDA approved and off patent, and intend to test for cryptic properties (HbF induction) in cells and sickle cell mice. Should these preliminary tests be fruitful, we will in the future then initiate clinical trials in ealthy and sickle cell patients.