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.

项目概要 β-血红蛋白病是全世界最常见的遗传性血液疾病，但有效的方法有限过去三十年来已经开发出诱导正常但发育沉默的治疗方法。胎儿血红蛋白 (HbF) 的表达可减少贫血并改善镰状细胞病 (SCD) 的临床严重程度。组蛋白脱乙酰酶 (HDAC) 已被证明可促进成人胎儿 γ-珠蛋白基因的沉默红细胞和 HDAC 抑制剂被证明会增加 β-血红蛋白病患者的 HbF。由于需要静脉内给药及其抗药性，这些药物应用受到限制。该项目的重点是创造安全有效的小分子口服 HbF 诱导剂。在一项研究中，我们观察了丁酸 (BA) 和 δ-氨基乙酰丙酸盐的新型口服结合物对 HbF 的诱导作用 (ALA)，命名为 AN-233，以及一种 BACH1 抑制剂，可增强镰状红细胞祖细胞中 NRF2 的表达接下来，我们将重点关注这些小分子药物，检验中心假设：通过表观遗传组蛋白修饰和增强 NRF2 结合调节 γ-球蛋白基因转录介导 HbF 诱导具体目标 1. 将测试口服前药 AN-233 诱导 HbF 的预测。使用相关的临床前研究，通过表观遗传组蛋白修饰和 NRF2 激活来表达在 β-YAC 和 SCD 转基因小鼠中进行的治疗将确定最佳口服剂量。以及诱导 HbF 而不产生抗增殖作用的 AN233 的时间表。 AN-233在SCD小鼠中与氧化应激相关，其抗镰状化能力将被测试以达到指标。我们将在贫血幼年狒狒身上测试 AN-233，以确定 HbF 的诱导和效果我们将定义 AN-233 涉及表观遗传组蛋白激活 γ-珠蛋白的机制。乙酰化以及 ALA 在血红素合成和 NRF2 激活中的作用具体目标 2. 测试预测。口服 BACH1 抑制剂 HPP-D 增强 NRF2 与 γ-珠蛋白启动子 ARE 的结合，从而激活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。并与临床相关药物（包括羟基脲和地西他滨）进行联合药物治疗。随后，HPP-D 通过增强 NRF2 在 γ- 中的结合诱导 HbF 的分子机制最后，将评估 HPP-D 在临床前 SCD 中诱导 HbF 表达的能力。小鼠将建立体内功效，包括建立特定的有效 HDAC 抑制剂和调节 β-珠蛋白位点染色质结构以有利于 γ-珠蛋白转录的药物，用于后续临床旨在解决改善 SCD 疾病缓解疗法的未满足需求的研究。