Development of fetal hemoglobin inducers targeting epigenetic and oxidative stress mechanisms

针对表观遗传和氧化应激机制的胎儿血红蛋白诱导剂的开发

基本信息

批准号：
10385817
负责人：
Betty Sue Pace
金额：
$ 36.2万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-20 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10385817
关键词：
Abnormal Hemoglobins Address Adherence Adolescent Adult Africa South of the Sahara Aminolevulinate Anemia Animal Model Annexins Antioxidants Apoptosis BACH1 gene Binding Biological Availability Biological Models Bone Marrow Butyric Acids CD34 gene Cells Chromatin Structure Clinical Clinical Research Clinical Trials Competitive Binding Country Data Decitabine Deoxyribonuclease I Development Disease Dose Drug Combinations Drug Kinetics Embryo Epigenetic Process Erythroid Cells Erythropoiesis Experimental Models FDA approved Fetal Development Fetal Hemoglobin Fright Fumarates Future Gene Activation Gene Expression Regulation Genes Genetic Genetic Transcription Goals Half-Life Hematological Disease Hematopoiesis Heme Hemoglobin Hemoglobinopathies Histone Acetylation Histone Deacetylase Histone Deacetylase Inhibitor Human Hypersensitivity Individual Infant Inherited Investigational Drugs Knockout Mice Knowledge Legal patent Locus Control Region Mediating Molecular Mus Names Oral Outcome Oxidative Stress Pain Papio Pathway interactions Patients Pattern Pharmaceutical Preparations Pharmacologic Substance Pharmacotherapy Phase I Clinical Trials Phenotype Plasma Population Prodrugs Proteins Response Elements Rest Role Schedule Severities Sickle Cell Anemia Site Source Stains Stem cell transplant TFRC gene Testing Toxic effect Transgenic Mice Transgenic Organisms United States Work base beta Globin chemotherapy clinically relevant cost drug development drug efficacy effective therapy erythroid differentiation fetal gamma Globin gene therapy histone modification hydroxyurea improved in vivo inhibitor intravenous administration mouse model novel pre-clinical progenitor promoter sickle erythroid sickling small molecule stem cells translational impact translational study transplantation therapy

项目摘要

PROJECT SUMMARY The β-hemoglobinopathies are the most common genetic blood disorders worldwide, but limited effective treatments have been developed over the last three decades. Induction of normal, but developmentally silenced fetal hemoglobin (HbF) expression reduces anemia and ameliorates clinical severity of sickle cell disease (SCD). Histone deacetylases (HDACs) have been shown to promote silencing of the fetal γ-globin genes in adult erythroid cells, and HDAC inhibitors were shown to increase HbF in patients with β-hemoglobinopathies. But these had limitations for pharmaceutical application due to the need for intravenous administration and their anti- proliferative effects. This project focuses on creating safe and effective small-molecule oral HbF-inducing agents. In one study, we observed HbF induction with a novel oral conjugate of butyric acid (BA) and δ-aminolevulinate (ALA), named AN-233, and a BACH1 inhibitor that enhanced NRF2 expression in sickle erythroid progenitors and β-YAC mice. Next, focusing on these small-molecule agents, we will test the central hypothesis that modulation of γ-globin gene transcription through epigenetic histone modifications and enhanced NRF2 binding mediate HbF induction. Specific Aim 1. will test the prediction that the oral prodrug AN-233 induces HbF expression through epigenetic histone modifications and NRF2 activation, using relevant preclinical animal models. Treatments conducted in β-YAC and SCD transgenic mice will establish the optimal oral dose and schedule of AN233 that induces HbF without producing anti-proliferative effects. The phenotypic effects of AN-233 in SCD mice related to oxidative stress, and its anti-sickling ability will be tested. To achieve an indicator of human drug efficacy we will test AN-233 in anemic juvenile baboon to determine HbF induction and effects on hematopoiesis. We will define mechanisms of γ-globin activation by AN-233 involving epigenetic histone acetylation and the role of ALA in heme synthesis and NRF2 activation. Specific Aim 2. Test the prediction that the oral BACH1 inhibitor HPP-D enhances NRF2 binding to the γ-globin promoter ARE to activate transcription. We will establish the BACH1 inhibitor HPP-D, as an HbF inducer using sickle erythroid progenitors and conduct combination drug treatments with clinically relevant agents including hydroxyurea and decitabine. Subsequently, molecular mechanisms of HbF induction by HPP-D through enhanced NRF2 binding in the γ- globin promoter will be evaluated. Finally, the ability of HPP-D to induce HbF expression in the preclinical SCD mice will establish in vivo efficacy. Expected outcomes include establishing specific potent HDAC inhibitors and agents that modulate β-globin locus chromatin structure in favor of γ‐globin transcription, for subsequent clinical studies to address the unmet need for improved disease-modifying therapy for SCD.

项目摘要 β-血红蛋白病是全球最常见的遗传性血液疾病，但有效有限在过去的三十年中，已经开发了治疗。诱导正常，但发达了沉默胎儿血红蛋白（HBF）表达可减少贫血并改善镰状细胞病（SCD）的临床严重程度。已经显示组蛋白脱乙酰基酶（HDAC）促进成人胎儿γ-球蛋白基因的沉默 β-血红蛋白病患者的红细胞细胞和HDAC抑制剂可增加HBF。由于需要静脉给药及其抗抗药性，因此这些局限增殖作用。该项目着重于创建安全有效的小分子口服HBF诱导剂。在一项研究中，我们观察到HBF诱导的丁酸（BA）和δ-氨基苯甲酸的新型口服结合物（ALA），命名为AN-233和Bach1抑制剂，可增强镰状红细胞祖细胞中NRF2的表达和β-yac小鼠。接下来，关注这些小分子剂，我们将测试中心假设通过表观遗传组蛋白的修饰和增强的NRF2结合对γ-球蛋白基因转录的调节介导HBF诱导。具体目标1。将测试口头前药AN-233归纳HBF的预测使用相关的临床前，通过表观遗传组蛋白的修饰和NRF2激活表达动物模型。在β-YAC和SCD转基因小鼠中进行的治疗将建立最佳的口服剂量和AN233的时间表，该AN233影响HBF而不会产生抗增殖作用。表型的作用与氧化应激有关的SCD小鼠中的AN-233及其抗溶能能力将被测试。达到指标人类药物有效性我们将在贫血幼狒狒中测试AN-233，以确定HBF诱导和影响在造血。我们将通过涉及表观遗传组蛋白的AN-233定义γ-球蛋白激活的机制乙酰化和ALA在血红素合成和NRF2激活中的作用。特定目标2。测试预测口服BACH1抑制剂HPP-D增强了NRF2与γ-球蛋白启动子的结合以激活转录。我们将使用镰状红细胞祖细胞建立Bach1抑制剂HPP-D作为HBF诱导剂并与临床相关的药物（包括羟基脲和决定性）进行联合药物处理。随后，HPP-D通过增强的NRF2结合在γ-中诱导HBF的分子机制将评估球蛋白启动子。最后，HPP-D在临床前SCD中诱导HBF表达的能力小鼠将建立体内效率。预期结果包括建立特定潜在的HDAC抑制剂和调节β-珠蛋白基因座染色质结构的药物有利于γ-球蛋白转录，以便随后的临床解决了改善SCD疾病改良疗法的未满足需求的研究。