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.

项目摘要/摘要成人红细胞细胞中胎儿血红蛋白表达的重新激活是遗传的验证方法 B-心中贫血和镰状细胞病（SCD）的治疗。但是，由于目前的实践基因疗法（慢病毒递送或CRISPR/CAS9编辑）无法满足大型疾病由于依赖造血性的患者的骨髓性预处理而导致的负担该程序的重建和医学密集型性质。药物（小分子）需要治疗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-珠蛋白基因的表达，并强劲地做到这一点安全。最有效的，经过验证的G-Globin表达的阻遏物是BCL11A。在这个项目中我们将扩展我们最近利用靶向蛋白的新化学方法的研究降解（TPD）耗尽BCL11A并重新激活HBF。该项目由两个广泛的目标。首先，我们将使用平台在可以分离出细胞周期不同阶段的红细胞细胞以进行新生转录分析。然后，使用BCl11a的急性TPD，我们将在细胞周期G-的哪个阶段确定（HBG）丢失阻遏物后，球蛋白被重新激活。这些数据将提供时间分辨率在前所未有的分辨率下的球蛋白基因转录。在第二个目标中，我们将探索使用红细胞特异性的E3泛素连接酶TRIM10和TRIM58，以靶向Bcl11a的降解。这 TIRIM蛋白将通过BCL11A特异性纳米构作用到BCL11A。我们将启动发现修剪蛋白的配体的配体，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。我们的工作将为新颖的小分子方法奠定基础对于血红蛋白疾病的HBF的稳健和安全重新激活。