Targeting ZNF410 for HbF reactivation

靶向 ZNF410 进行 HbF 重新激活

基本信息

批准号：
10608727
负责人：
Daniel Evan Bauer
金额：
$ 69.17万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-01 至 2027-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10608727
关键词：
Address Adult Affect Alleles Animal Model Animals Binding Biological Biological Assay Biological Process Bypass CHD4 gene CRISPR screen Cell model Cells Chemicals Chromatin Clinical Clinical Trials Dedications Defect Development Disease Elements Erythrocytes Erythroid Erythropoiesis Evaluation Event Exhibits Fetal Hemoglobin Future Gene Expression Gene Expression Regulation Gene Targeting Genes Genome Genomics Goals Growth Hematology Hematopoiesis Hematopoietic Hemoglobin Hemoglobin concentration result Hemoglobinopathies Homeostasis Human In Vitro Investigation Knock-out Lead Libraries Logic Mendelian disorder Molecular Molecular Genetics Molecular Target Mus Mutation NuRD complex Nucleosomes Orthologous Gene Pharmaceutical Chemistry Pharmacotherapy Phenotype Population Proteins Regulation Regulator Genes Regulatory Element Reporter Repression Rest Role Safety Sickle Cell Anemia Structure-Activity Relationship System TNFSF5 gene Therapeutic Therapeutic Index Toxic effect Transcription Repressor Upstream Enhancer Xenograft procedure beta Thalassemia derepression drug development functional genomics gamma Globin gene repression gene therapy health disparity hematopoietic engraftment immune modulating agents immunoregulation in vivo inhibitor lenalidomide mouse development novel pomalidomide promoter protein complex protein degradation scale up screening small molecule success targeted treatment therapeutic evaluation therapeutic target tool transcription factor ubiquitin ligase

项目摘要

ABSTRACT Hemoglobin disorders, such as sickle cell disease and β-thalassemia, comprise the most common monogenic diseases of the world and yet, current treatments remain largely supportive and inadequate. Induction of fetal hemoglobin (HbF) could bypass the fundamental genetic defects of adult hemoglobin that cause these diseases. Recent gene therapy successes provide proof-of-concept that understanding the molecular control of adult-stage HbF silencing can identify rational therapeutic targets. However, gene therapy cannot be scaled up globally to match the scope of the clinical problem for the foreseeable future. Therefore, novel pharmacotherapies are needed to induce HbF. The major HbF regulators BCL11A, ZBTB7A, and NuRD each have on-target liabilities that could make therapeutic targeting challenging. Recently ZNF410 was discovered to be a novel transcriptional repressor of HbF level during adult-stage erythropoiesis. ZNF410 has a narrow biological action, which is to enhance the expression of CHD4. CHD4 possesses a unique array of 27 reiterated ZNF410 binding motifs at its promoter and upstream enhancer, an assemblage without comparison in the rest of the genome. This study aims to investigate the: mechanisms whereby ZNF410 controls the expression of CHD4 through homotypic motif clusters; requirements for ZNF410 and its orthologs throughout development, homeostasis and hematopoiesis; and potential of targeted protein degradation of ZNF410 by IMiD congeners as a therapeutic approach. Near-term goals are to define the role of protein-level cooperativity and chromatin accessibility in binding to CHD4 by ZNF410 and the relationship between ZNF410 binding events and CHD4 expression. These mechanistic studies will help identify vulnerabilities in this regulatory axis that might be targeted therapeutically. Furthermore, the roles of ZNF410 throughout mouse development and adulthood as well as in human hematopoiesis will be investigated. Constitutive and conditional alleles of Zfp410 and its cognate regulatory elements at Chd4 in mice will be generated and characterized. Requirements for ZNF410 throughout human erythropoiesis and hematopoiesis will be identified by bulk and single cell gene expression and chromatin profiling in vitro and in vivo. Finally, tool compounds will be generated to validate targeted protein degradation of ZNF410 by small molecules as a promising therapeutic approach. Structural evaluation and systematic exploration of structure-activity relationships will be leveraged to obtain instructive compounds to evaluate in ZNF410/Zfp410 sufficient and deficient cellular and animal models the therapeutic premise that ZNF410 is a favorable therapeutic target for HbF induction in the β- hemoglobinopathies. The long-term goal is to promote the development of drug-like small molecules that ultimately could be used in clinical trials.

抽象的血红蛋白疾病（例如镰状细胞疾病和β-杜松子病）构成了最常见的单基因世界上的疾病，但目前的治疗仍得到支持和不足。胎儿的诱导血红蛋白（HBF）可以绕过成年血红蛋白的基本遗传缺陷疾病。最近的基因治疗成功提供了概念证明，了解成人阶段的HBF沉默可以识别有理治疗靶标。但是，基因疗法不能扩展在可预见的未来，全球范围内符合临床问题的范围。因此，新颖需要药物疗法来诱导HBF。主要的HBF监管机构BCL11A，ZBTB7A和NURD各自具有目标责任，可能会导致热靶向挑战。最近发现了Znf410 成为成人红细胞生成期间HBF水平的新型转录表示。 Znf410有一个狭窄的生物学作用，是为了增强CHD4的表达。 CHD4拥有27个独特的阵列在其启动子和上游增强子处重申Znf410结合基序，这是一个没有比较的组合在其余基因组中。这项研究旨在研究：Znf410控制的机制 CHD4通过同型基序簇的表达； Znf410及其直系同源物的要求发展，体内平衡和造血；和靶向蛋白质降解Znf410的潜力 IMID同类物作为一种治疗方法。近期目标是定义蛋白质水平协调的作用 Znf410与CHD4结合的染色质可及性以及Znf410结合之间的关系事件和CHD4表达。这些机械研究将有助于确定该法规轴的漏洞这可能是针对性的。此外，Znf410在整个小鼠发育和将研究成年和人类造血。构成和条件等位基因 ZFP410及其在小鼠中的CHD4的同源调节元素将被生成和表征。 Znf410整个人类红细胞生成和造血的要求将由批量确定单细胞基因表达和体内和体内染色质分析。最后，工具化合物将是生成以验证小分子作为一种有希望的治疗的Znf410的靶向蛋白质降解方法。结构评估和系统探索结构活性关系将被利用要获得具有启发性化合物以在Znf410/ZFP410中评估足够且缺陷的细胞和动物模拟ZnF410是HBF诱导β-的治疗前提的模型血红蛋白病。长期目标是促进类似药物的小分子的发展最终可以用于临床试验中。