In Vivo Studies of a Novel HDAC Inhibitor for Treating Hemoglobin Disorders

项目摘要 β-血红蛋白病是一种常见的遗传性血液病，治疗选择很少。据估计 世界上7%的人口携带异常血红蛋白基因，每年有40万婴儿出生时携带异常血红蛋白基因。 严重危及生命的血红蛋白病。药物介导的正常诱导，但发育沉默， 胎儿血红蛋白（HbF）表达可减少贫血并改善β- 血红蛋白病组蛋白去乙酰化酶（HDAC）1、2和3是CD 3D阻遏物的组分 复合物，其促进成人红系细胞中胎儿γ-珠蛋白基因的沉默。上一代HDAC 抑制剂增加β-血红蛋白病患者的HbF，但对药物治疗有局限性。 施用和/或需要滴定以降低抗增殖作用。Cetya已经产生了一个图书馆， 有效HDAC抑制剂，其中之一CT-101已证明在β-HDAC中诱导HbF表达的有效性。 地中海贫血和镰状细胞红系祖细胞以及含有正常 人β-珠蛋白基因位点，没有显著的抗增殖作用。我们将检验中心假设 CT-101具有足够宽的活性范围，对红系细胞生长没有显著抑制， 作为治疗β-血红蛋白病的新药开发。我们建议进行研究， CT-101在β-YAC模型中的作用，以优化剂量和时间表，然后确认在Townes镰状细胞中的疗效。 疾病小鼠模型。Cetya将扩大CT-101的制造工艺，并生产足够的数量， 支持小鼠研究和口服制剂开发。该项目的目标是开发新的 用于IND和临床治疗的高效HDAC抑制剂CT-101。为了验证我们的假设， 目标将完成。目标1.检验CT-101在临床前β-CD患者中诱导HbF表达的假设。 通过表观遗传组蛋白修饰的YAC和Townes镰状细胞病小鼠模型。目标2.缩放 生产工艺和生产足够数量的CT-101，以进行所需的IND使能研究 进行I期临床研究。目标3。CT-101口服剂型的研制 局该2期项目的预期结果是将CT-101开发为口服有效的HbF 诱导剂。我们的实验方法基于科学验证的镰刀抑制概念 通过HbF进行血红蛋白聚合和通过逆转众所周知的表观遗传γ-珠蛋白进行红细胞镰状化 基因沉默机制开发有效的HDAC抑制剂CT-101将影响该领域， 解决了对β-血红蛋白病的额外疾病改善疗法的未满足的需求。

PROJECT SUMMARY The β-hemoglobinopathies are prevalent genetic blood diseases with few treatment options. It is estimate that 7% of the world's population carries an abnormal hemoglobin gene with 400,000 infants born annually with a severe life threatening hemoglobinopathy. Drug mediated induction of normal, but developmentally silenced, fetal hemoglobin (HbF) expression reduces anemia and ameliorates clinical severity in the β- hemoglobinopathies. Histone deacetylase (HDAC) 1, 2, and 3, are components of the NURD repressor complex, which promotes silencing of the fetal γ-globin genes in adult erythroid cells. Prior generation HDAC inhibitors increase HbF in patients with β-hemoglobinopathies, but had limitations for pharmaceutical application and/or required titration to reduce anti-proliferative effects. Cetya has generated a library of high potency HDAC inhibitors, one of which, CT-101, has demonstrated efficacy in inducing HbF expression in β- thalassemia and sickle cell erythroid progenitors and in the β-YAC mouse model that contains the normal human β-globin gene locus,without significant anti-proliferative effects. We will test the central hypothesis that CT-101 has a sufficiently wide margin of activity, without significant inhibition of erythroid cell growth, to be developed as a new agent for treatment of β-hemoglobinopathies. We propose to conduct studies to evaluate CT-101 in the β-YAC model to optimize dose and schedule, and then confirm efficacy in the Townes sickle cell disease mouse model. Cetya will scale the CT-101 manufacturing process and produce sufficient quantities to support the murine studies and oral formulation development. The goal of this project is to develop the new high-potency HDAC inhibitor CT-101 for an IND and clinical therapeutics. To test our hypothesis the following aims will be completed. Aim 1. Test the hypothesis that CT-101 induces HbF expression in the preclinical β- YAC and Townes sickle cell disease mouse models through epigenetic histone modifications. Aim 2. Scale the manufacturing processes and produce sufficient quantities of CT-101 to conduct IND-enabling studies required for a Phase I clinical study. Aim 3. Develop an oral dosage formulation of CT-101 suitable for human administration. The expected outcome of this Phase 2 project is to develop CT-101 as an oral effective HbF inducer. Our experimental approach rests on the scientifically validated concept of the inhibition of sickle hemoglobin polymerization by HbF and red blood cell sickling by reversing a well-known epigenetic γ-globin gene silencing mechanism. Development of the potent HDAC inhibitor CT-101 will impact the field and addresses an unmet need for additional disease modifying therapy for β-hemoglobinopathies.