Inactivation of LSD1 as a possible treatment for sickle cell disease

描述（由申请人提供）：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。目前唯一的SCD治疗方法是使用羟基脲（HU）治疗。HU通过尚不清楚的机制在约一半的治疗患者中诱导胎儿血红蛋白（HbF）合成，并且其长期影响在很大程度上是未知的。临床上已知HbF诱导可降低SCD患者的器官发病率和疼痛，并抑制镰状聚合物形成，从而抑制体外红细胞破坏。在过去的十年里，我的实验室一直在研究一种叫做DRED的胎儿G-珠蛋白基因阻遏物。我们最近报道的亚基组成DRED，这是由至少四个不同的表观遗传修饰辅阻遏多蛋白复合物。其中一种修饰酶是LSD 1，一种单胺氧化酶，可去除激活的染色质标记，从而导致基因抑制。我们最近测试了一种高度特异性的LSD 1抑制剂，称为反苯环丙胺（TC）。我们发现，在体外诱导分化为红系细胞的人CD 34+造血干细胞中，HbF以TC剂量依赖性方式被诱导至治疗水平。我们已经为TC申请了一项新的用途专利，该专利已经获得FDA批准，并打算在细胞和镰状细胞小鼠中测试隐藏特性（HbF诱导）。如果这些初步的测试是富有成效的，我们将在未来开始在健康和镰状细胞患者中进行临床试验。 公共卫生相关性：血红蛋白病是人类最常见的遗传性疾病，相关的临床证据表明，g-珠蛋白替代镰状红细胞中的bS珠蛋白对SCD具有治疗作用。一个可行的有吸引力的策略，以诱导g-珠蛋白合成将是去乙酰化的调节蛋白，通常功能抑制g-珠蛋白合成在成人红系前体细胞。我们最近确定了酶LSD 1作为一个核心G-珠蛋白阻遏复合物的组成部分之一。最近，我们发现，在诱导分化为红系细胞的人CD 34+造血干细胞中，通过LSD 1 mRNA降解或抑制LSD 1催化作用降低细胞内LSD 1活性导致离体胎儿血红蛋白水平的显著诱导。该提案探讨了最初的假设，即FDA批准的抗抑郁药Parnate可用于治疗SCD。

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. PUBLIC HEALTH RELEVANCE: Hemoglobinopathies are the most common inherited disorders in man. Correlative clinical evidence suggests that g-globin replacing bS globin in sickle red cells is therapeutic for SCD. A feasibly attractive strategy to induce g-globin synthesi would be to inactivate a regulatory protein that normally functions to repress g-globin synthesis in adult erythroid precursor cells. We recently identified the enzyme LSD1 as one of the components of a core g-globin repressor complex. Most recently, we discovered that in human CD34+ hematopoietic stem cells induced to differentiate into erythroid cells, reduction of intracellular LSD1 activity via LSD1 mRNA degradation or inhibition of LSD1 catalytic action led to dramatic induction of fetal hemoglobin levels ex vivo. This proposal explores the initial hypothesis that Parnate, an FDA-approved antidepressant, could be used to treat SCD.