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:
  • 金额:
    $ 69.17万
  • 依托单位:
  • 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

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。

项目成果

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Daniel Evan Bauer其他文献

Daniel Evan Bauer的其他文献

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{{ truncateString('Daniel Evan Bauer', 18)}}的其他基金

Chemotherapy-free cure of hemoglobin disorders through base editing
通过碱基编辑无需化疗即可治愈血红蛋白疾病
  • 批准号:
    10754114
  • 财政年份:
    2023
  • 资助金额:
    $ 69.17万
  • 项目类别:
Structural Variation and Hematological Traits
结构变异和血液学特征
  • 批准号:
    10657020
  • 财政年份:
    2023
  • 资助金额:
    $ 69.17万
  • 项目类别:
Comprehensive characterization of variants underlying heart and blood diseases with CRISPR base editing
通过 CRISPR 碱基编辑全面表征心脏和血液疾病的变异
  • 批准号:
    10296877
  • 财政年份:
    2021
  • 资助金额:
    $ 69.17万
  • 项目类别:
Comprehensive characterization of variants underlying heart and blood diseases with CRISPR base editing
通过 CRISPR 碱基编辑全面表征心脏和血液疾病的变异
  • 批准号:
    10473734
  • 财政年份:
    2021
  • 资助金额:
    $ 69.17万
  • 项目类别:
Comprehensive characterization of variants underlying heart and blood diseases with CRISPR base editing
通过 CRISPR 碱基编辑全面表征心脏和血液疾病的变异
  • 批准号:
    10627940
  • 财政年份:
    2021
  • 资助金额:
    $ 69.17万
  • 项目类别:
Gene editing ELANE to understand and treat severe congenital neutropenia
基因编辑 ELANE 了解和治疗严重先天性中性粒细胞减少症
  • 批准号:
    10580862
  • 财政年份:
    2020
  • 资助金额:
    $ 69.17万
  • 项目类别:
Therapeutic BCL11A enhancer gene editing to induce fetal hemoglobin in β-hemoglobinopathy patients
治疗性 BCL11A 增强子基因编辑诱导 β 血红蛋白病患者胎儿血红蛋白
  • 批准号:
    10317505
  • 财政年份:
    2020
  • 资助金额:
    $ 69.17万
  • 项目类别:
Therapeutic BCL11A enhancer gene editing to induce fetal hemoglobin in β-hemoglobinopathy patients
治疗性 BCL11A 增强子基因编辑诱导 β 血红蛋白病患者胎儿血红蛋白
  • 批准号:
    10090251
  • 财政年份:
    2020
  • 资助金额:
    $ 69.17万
  • 项目类别:
Gene editing ELANE to understand and treat severe congenital neutropenia
基因编辑 ELANE 了解和治疗严重先天性中性粒细胞减少症
  • 批准号:
    10338097
  • 财政年份:
    2020
  • 资助金额:
    $ 69.17万
  • 项目类别:
Rectifying splicing mutations in blood disorders by gene editing
通过基因编辑纠正血液疾病中的剪接突变
  • 批准号:
    10531577
  • 财政年份:
    2019
  • 资助金额:
    $ 69.17万
  • 项目类别:

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