Non-cytotoxic augmentation of fetal hemoglobin and bone marrow reserves

非细胞毒性增加胎儿血红蛋白和骨髓储备

基本信息

批准号：
10627767
负责人：
Yogen Saunthararajah
金额：
$ 102.31万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10627767
关键词：
ATPase Domain Address Adult Biological Availability Biological Markers Bone Marrow CHD4 gene Cells Cessation of life Clinic Clinical Coagulation Process Cytotoxic agent DNA Modification Methylases Decitabine Drug Design Drug Targeting Drug usage Enhancers Enzyme Inhibition Enzyme Repression Enzymes Erythrocytes Erythroid Erythropoiesis Evaluation Family Fetal Hemoglobin Frequencies Genes Genetic Polymorphism Genetic Transcription Glutamine Goals Half-Life Hematopoietic Hematopoietic stem cells Hemoglobin Hemoglobin concentration result Hemolysis Human ISWI In Vitro Individual Inflammation Inherited Life Locus Control Region Marrow Mediator Methods Modeling Molecular Target Morbidity - disease rate Mus Natural experiment Niacinamide Nucleosomes Oral Outcome Output Patient Outcomes Assessments Patients Pharmaceutical Preparations Positioning Attribute Proliferating Protocols documentation Quality of life Randomized Recovery Refractory Regulation Repression Reserve Stem Cell Risk Safety Sickle Cell Anemia Stress Structure Supplementation System Tetrahydrouridine Time Translating Water Work beta Globin chromatin remodeling cytotoxicity design experience gamma Globin hematopoietic differentiation high risk hydroxyurea in vivo infancy inhibitor innovation interest mortality nonhuman primate novel novel therapeutics pre-clinical preservation progenitor small molecule

ATPase Domain Address Adult Biological Availability Biological Markers Bone Marrow CHD4 gene Cells Cessation of life Clinic Clinical Coagulation Process Cytotoxic agent DNA Modification Methylases Decitabine Drug Design Drug Targeting Drug usage Enhancers Enzyme Inhibition Enzyme Repression Enzymes Erythrocytes Erythroid Erythropoiesis Evaluation Family Fetal Hemoglobin Frequencies Genes Genetic Polymorphism Genetic Transcription Glutamine Goals Half-Life Hematopoietic Hematopoietic stem cells Hemoglobin Hemoglobin concentration result Hemolysis Human ISWI In Vitro Individual Inflammation Inherited Life Locus Control Region Marrow Mediator Methods Modeling Molecular Target Morbidity - disease rate Mus Natural experiment Niacinamide Nucleosomes Oral Outcome Output Patient Outcomes Assessments Patients Pharmaceutical Preparations Positioning Attribute Proliferating Protocols documentation Quality of life Randomized Recovery Refractory Regulation Repression Reserve Stem Cell Risk Safety Sickle Cell Anemia Stress Structure Supplementation System Tetrahydrouridine Time Translating Water Work beta Globin chromatin remodeling cytotoxicity design experience gamma Globin hematopoietic differentiation high risk hydroxyurea in vivo infancy inhibitor innovation interest mortality nonhuman primate novel novel therapeutics pre-clinical preservation progenitor small molecule

展开

项目摘要

ABSTRACT SCD patients require erythropoiesis >10-fold over normal to barely sustain hemoglobin levels compatible with life, and dwindling compensatory capacity is a major cause of early death. Therefore, our overall goal in Project 3 is to develop methods of inducing HbF that are non-cytotoxic and preserve or even increase marrow reserves. Biologically undergirding our approach is the `maturational switch': the switch of the shared enhancer from γ- globin (HBG) to the adult β-globin gene (HBB) during non-fetal erythropoiesis, a switch that first requires acquisition of repressive marks at HBG. As examined in Project 1, the repressive marks are catalyzed by druggable enzymes, e.g. DNMT1, and inhibiting these enzymes favors the LCR interaction with HBG, producing significant HbF increases even in patients with severe, HU-refractory SCD. Moreover, as examined in Project 2, treatments that retard erythroid maturation can potentially widen the maturation-stage window for inhibition of repressing enzymes, enabling greater HbF inductions while simultaneously increasing RBC output per progenitor, relieving some of the demands on dwindling and precious marrow stem cell reserve. This highly innovative but rational concept is evaluated clinically for the first time in Aim 1, by combining nicotinamide (vit.B3), which retards hematopoietic maturation but not proliferation, is very well-tolerated, and is a major mediator of the benefits of glutamine supplementation in SCD, with THU-decitabine, a novel orally bioavailable non-cytotoxic drug that targets DNMT1. Aim 2 addresses a more obvious concept, that although any HbF induction is potentially beneficial, achieving maximum protection with HbF ~30% may require combining inhibitors of individual HBG repressing enzymes. The culmination of chromatin remodeling for repression is nucleosome repositioning that physically denies access to the basal transcription machinery. This energetically expensive work is executed by ISWI family enzymes, e.g., CHD4 (Project 1). CHD4 inhibition should hence offer corresponding potency for HbF induction. We have therefore screened for and optimized through structure-aided design a first-in-class CHD4 inhibitor - we will evaluate this inhibitor for HbF inducing potency and drive toward IND-enabling. Aim 1: Conduct a proof-of-concept study of oral nicotinamide (vitamin B3) and oral THU- decitabine, alone and in combination, to treat severe SCD. This proof-of-concept study of combination non- cytotoxic oral therapy to both induce HbF and augment bone marrow reserves will randomize adult SCD patients at risk of early death to nicotinamide or oral THU-decitabine alone. Aim 2: Determine the HbF inducing potency of small molecule CHD4 inhibition in vitro and in vivo, to justify IND-enabling studies. We will employ primary cell ex vivo systems to compare the HbF inducing potency of the novel drug vs established agents, followed by evaluation in SCD mice (Project 1), and finally in non-human primate models (Project 2). Hence, candidate molecular targets for simultaneous induction of HbF and augmentation of bone marrow reserve, identified and validated in Projects 1 & 2, are translated into or toward the clinic by Project 3.

抽象的 SCD患者需要促红细胞生成率>正常> 10倍，以勉强维持与兼容的血红蛋白水平生命和减少补偿能力是提早死亡的主要原因。因此，我们在项目中的总体目标 3是开发非毒性并保存甚至增加骨髓储量的诱导HBF方法。生物学下的生物少于我们的方法是“成熟开关”：共享增强子从γ-的转换在非爆发红细胞生成期间，球蛋白（HBG）到成年β-珠蛋白基因（HBB），首先需要的开关在HBG上获得反射标记。如项目1所述，反射标记是由可吸毒的酶，例如DNMT1，并抑制这些酶有利于LCR与HBG的相互作用，从而产生即使在严重的Hu-Rcractory SCD患者中，HBF也会增加。而且，正如项目中所检查的 2，延迟红斑成熟的治疗方法可能会宽阔的成熟阶段窗口以抑制抑制酶，实现更大的HBF诱导，同时增加RBC输出祖先，减轻了对减少和珍贵的骨髓干细胞储备的一些要求。这很高创新但理性的概念在AIM 1中首次通过结合烟酰胺（VIT.B3），首次在AIM上进行评估。降低了造血成熟而不是增殖，非常耐受，是 SCD中补充谷氨酰胺的好处，thu-decitabine是一种新颖的口服生物可用性非毒性的。针对DNMT1的药物。 AIM 2解决了一个更明显的概念，尽管任何HBF诱导是潜在的有益，以HBF〜30％实现最大保护可能需要合并抑制剂单个HBG抑制酶。染色质重塑以反射的顶点是核小体重新定位物理上拒绝访问基本转录机械的位置。这有效昂贵工作由ISWI家族酶执行，例如CHD4（项目1）。 CHD4抑制应因此提供 HBF诱导的相应效力。因此，我们已经筛选并通过结构AID进行了优化设计一流的CHD4抑制剂 - 我们将评估该抑制剂的HBF诱导效力并朝向索引。 AIM 1：进行口服烟酰胺（维生素B3）和口服THU-的概念验证研究单独和组合的解替滨，以治疗严重的SCD。这项概念概念性研究非 - 诱导HBF和增强骨髓储量的细胞毒性口服疗法将随机成人SCD患者只有早期死亡的烟酰胺或口服thu-decitabine的风险。目标2：确定HBF诱导小分子CHD4体外和体内抑制的效力，以证明辅助研究是合理的。我们将员工初级细胞离体系统比较了HBF引起的新型药物与建立的效力代理，然后在SCD小鼠中进行评估（项目1），最后是非人类灵长类动物模型（项目2）。因此，同时诱导HBF和骨髓增强的候选分子靶在项目1和2中确定和验证的储备被项目3转化为诊所。