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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