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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.

摘要血红蛋白疾病，如镰状细胞病和β-地中海贫血，包括最常见的单基因然而，目前的治疗在很大程度上仍然是支持性的和不充分的。胎儿引产血红蛋白（HbF）可以绕过成人血红蛋白的基本遗传缺陷，导致这些疾病最近的基因治疗成功提供了概念验证，即了解基因治疗的分子控制。成年期HbF沉默可以鉴定合理的治疗靶点。然而，基因治疗不能扩大规模，以在可预见的未来与临床问题的范围相匹配。因此，小说需要药物治疗来诱导HbF。主要的HbF调节剂BCL 11 A、ZBTB 7A和NuRD各自具有靶向缺陷，这可能使治疗靶向具有挑战性。最近，ZNF 410被发现是一个新的成年期红细胞生成过程中HbF水平的转录抑制因子。ZNF 410具有窄生物学作用，即增强CHD 4的表达。CHD 4拥有一个27的独特数组在ZNF 410的启动子和上游增强子处重复了ZNF 410结合基序，这是一个没有比较的组合在基因组的其余部分。本研究旨在探讨：ZNF 410控制肿瘤生长的机制通过同型基序簇表达CHD 4;对ZNF 410及其直系同源物的要求发育，稳态和造血;和ZNF 410的靶向蛋白质降解的潜力， IMiD同系物作为一种治疗方法。近期目标是确定蛋白质水平协同性的作用 ZNF 410与CHD 4结合的染色质可及性以及ZNF 410与CHD 4结合事件和CHD 4表达。这些机制研究将有助于确定这一监管轴心的漏洞可能是治疗的目标。此外，ZNF 410在小鼠发育过程中的作用以及将研究成年期以及人造血中的作用。组成型和条件型等位基因将产生并表征小鼠中Chd 4的Zfp 410及其同源调控元件。将通过原液和细胞培养确定整个人红细胞生成和造血过程中对ZNF 410的需求。体外和体内单细胞基因表达和染色质谱分析。最后，工具化合物将用于验证小分子对ZNF 410的靶向蛋白降解作为一种有前途的治疗方法 approach.将利用结构评价和结构-活动关系的系统探索获得指导性化合物，以评价ZNF 410/Zfp 410中的足够和缺乏的细胞和动物模型的治疗前提是ZNF 410是一个有利的治疗靶点HbF诱导的β- 血红蛋白病长期目标是促进药物样小分子的开发，最终可以用于临床试验。