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DEGRADATION OF BCL11A PROTEIN FOR HbF REACTIVATION

BCL11A 蛋白降解以促进 HbF 重新激活

基本信息

批准号：
10733620
负责人：
STUART H ORKIN
金额：
$ 38.6万
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：
2023-08-07 至 2028-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10733620
关键词：
Acute Address Adult Affect Back Binding Binding Sites CD34 gene CRISPR/Cas technology Cell Cycle Cells Chemicals Clinical Clinical Trials Data Development Disease Down-Regulation Erythrocytes Erythroid Erythroid Cells Evolution Fetal Hemoglobin Fetal Proteins Gene Delivery Gene Expression Gene Modified Gene therapy trial Genes Genetic Transcription Geographic Locations Globin Goals Hematology Hematopoietic Hemoglobin Hereditary Disease Laboratories Ligands Medical Methods Methylation Modality Nature Oxygen Patients Pharmaceutical Preparations Phase Procedures Production Proteins Research Resolution Resources Role Sickle Cell Anemia TRIM Gene Therapeutic Transfusion Validation Vision Work activity-based protein profiling base editing beta Thalassemia burden of illness derepression gene therapy global health in vivo innovation nanobodies novel novel therapeutic intervention novel therapeutics pharmacologic preconditioning promoter protein degradation reconstitution small hairpin RNA small molecule small molecule therapeutics symptomatology temporal measurement therapeutic target tool ubiquitin-protein ligase

项目摘要

Project Summary/Abstract Reactivation of fetal hemoglobin expression in adult erythroid cells is a validated approach to genetic therapy of both b-thalassemia and sickle cell disease (SCD). As currently practiced, however, genetic therapy (either lentiviral delivery or CRISPR/Cas9 editing) cannot meet the large disease burden due to its reliance on myeloablative preconditioning of patients for hematopoietic reconstitution and the medically intensive nature of the procedure. Drug (small molecule) therapeutics are needed to treat the many patients with these disorders. The vision of our research is to use small molecule therapeutics to reactivate y-globin gene expression, and do so both robustly and safely. The most potent, validated repressor of g-globin expression is BCL11A. In this project we will extend our recent studies in which we leveraged new chemical methods of targeted protein degradation (TPD) to deplete BCL11A and reactivate HbF production. The project consists of two broad aims. First, we will determine the dynamics of globin gene transcription using a platform in which erythroid cells at different phases of the cell cycle can be isolated for nascent transcription analyses. Using acute TPD of BCL11A, we will then ascertain at which stage(s) of the cell cycle g- (HBG) globin is reactivated upon loss of the repressor. These data will provide temporal resolution of globin gene transcription at unprecedented resolution. In a second aim, we will explore the use of erythroid-specific E3 ubiquitin ligases, TRIM10 and TRIM58, to target degradation of BCL11A. The TRIM proteins will be directed to BCL11A with BCL11A-specific nanobodies. We will initiate discovery of ligands for the TRIM proteins in order to develop tool compounds for cell-specific TPD of BCL11A as a new therapeutic strategy. Our work will lay the groundwork for novel small molecule approaches for robust and safe reactivation of HbF for the hemoglobin disorders.

项目概要/摘要成人红细胞中胎儿血红蛋白表达的重新激活是一种经过验证的遗传方法治疗β地中海贫血和镰状细胞病（SCD）。然而，按照目前的做法，基因治疗（无论是慢病毒递送还是CRISPR/Cas9编辑）都无法应对大疾病由于其依赖于患者的造血清髓预处理而造成负担重建和手术的医疗密集性质。药物（小分子）需要治疗方法来治疗许多患有这些疾病的患者。我们研究的愿景是使用小分子疗法重新激活 y 球蛋白基因表达，并且稳健地实现这一点并安全。最有效、经过验证的 g-珠蛋白表达抑制因子是 BCL11A。在这个项目中我们将扩展我们最近的研究，其中我们利用了目标蛋白质的新化学方法降解 (TPD) 以耗尽 BCL11A 并重新激活 HbF 产生。该项目由两部分组成广泛的目标。首先，我们将使用以下平台确定珠蛋白基因转录的动态可以分离细胞周期不同阶段的红细胞进行新生转录分析。使用 BCL11A 的急性 TPD，我们将确定细胞周期的哪个阶段 g- (HBG) 珠蛋白在阻遏蛋白丢失后重新激活。这些数据将提供时间分辨率以前所未有的分辨率进行珠蛋白基因转录。在第二个目标中，我们将探索使用红细胞特异性 E3 泛素连接酶 TRIM10 和 TRIM58，以降解 BCL11A。这 TRIM 蛋白将通过 BCL11A 特异性纳米抗体定向至 BCL11A。我们将发起发现 TRIM 蛋白的配体，以开发 BCL11A 细胞特异性 TPD 的工具化合物作为一种新的治疗策略。我们的工作将为新型小分子方法奠定基础用于针对血红蛋白疾病稳健且安全地重新激活 HbF。