Inactivation of LSD1 as a possible treatment for sickle cell disease

LSD1 失活作为镰状细胞病的可能治疗方法

• 批准号: 8319822
• 负责人: James Douglas Engel
• 金额: $ 23.33万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8319822
• 关键词: Accident and Emergency department; Acute Pain; Adult; Adverse effects; Affect; African American; Alleles; American; Amphetamines; Antidepressive Agents; Birth; Bone Marrow Transplantation; CD34 gene; Cells; Cessation of life; Characteristics; Child; Chromatin; Chronic; Clinical; Clinical Management; Clinical Trials; Code; Complex; Dehydration; Depressed mood; Disease; Disease Management; Employee Strikes; Enhancers; Enzymes; Epidemiology; Epigenetic Process; Erythrocytes; Erythroid Cells; Erythroid Progenitor Cells; Event; Exhibits; FDA approved; Failure; Fetal Hemoglobin; Frequencies; Future; Genes; Genetic; Globin; Hematopoietic stem cells; Hemoglobin; Hemoglobin F Disease; Hemoglobin concentration result; Hemoglobinopathies; Hemolytic Anemia; Hereditary Disease; Heterozygote; Histone H3; Hospitalization; Human; In Vitro; Inborn Genetic Diseases; Indium; Individual; Infant; Infarction; Inherited; Iron Chelation; Laboratories; Lead; Legal patent; Lesion; Life; Literature; Long-Term Effects; Lysine; Malignant Neoplasms; Missense Mutation; Mono-S; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Morbidity - disease rate; Multiprotein Complexes; Mus; Names; Organ; Oxygen measurement, partial pressure, arterial; Pain; Parnate; Patients; Peptide Signal Sequences; Pharmaceutical Preparations; Polymers; Predisposition; Property; RNA Splicing; Reporting; Risk; Sickle Cell; Sickle Cell Anemia; Stress; Testing; Thalassemia; Therapeutic; Transfusion; Tranylcypromine; Ursidae Family; Visit; adverse outcome; dosage; erythroid differentiation; experience; fetal; gene repression; genetic regulatory protein; hydroxyurea; inhibitor/antagonist; mRNA Transcript Degradation; man; mimetics; mutant; novel; polymerization; promoter; sickling

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.

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。 与公共卫生相关：血红蛋白疾病是人类最常见的遗传性疾病。相关临床证据表明，镰状红细胞中的G-珠蛋白替代BS-珠蛋白对SCD有治疗作用。诱导G-珠蛋白合成的一个可行的有吸引力的策略是使一种调节蛋白失活，该蛋白通常作用于抑制成人红系前体细胞中的G-珠蛋白合成。我们最近发现LSD1酶是核心g-珠蛋白抑制物复合体的一种成分。最近，我们发现在被诱导分化为红系细胞的人CD34+造血干细胞中，通过LSD1mRNA降解降低细胞内LSD1活性或抑制LSD1催化作用导致体外显著诱导胎儿血红蛋白水平。这项建议探索了最初的假设，即FDA批准的抗抑郁药帕拉特可以用于治疗SCD。