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:
- 金额:$ 38.6万
- 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:2023-08-07 至 2028-07-31
- 项目状态:未结题
- 来源:
- 关键词:AcuteAddressAdultAffectBackBindingBinding SitesCD34 geneCRISPR/Cas technologyCell CycleCellsChemicalsClinicalClinical TrialsDataDevelopmentDiseaseDown-RegulationErythrocytesErythroidErythroid CellsEvolutionFetal HemoglobinFetal ProteinsGene DeliveryGene ExpressionGene ModifiedGene therapy trialGenesGenetic TranscriptionGeographic LocationsGlobinGoalsHematologyHematopoieticHemoglobinHereditary DiseaseLaboratoriesLigandsMedicalMethodsMethylationModalityNatureOxygenPatientsPharmaceutical PreparationsPhaseProceduresProductionProteinsResearchResolutionResourcesRoleSickle Cell AnemiaTRIM GeneTherapeuticTransfusionValidationVisionWorkactivity-based protein profilingbase editingbeta Thalassemiaburden of illnessderepressiongene therapyglobal healthin vivoinnovationnanobodiesnovelnovel therapeutic interventionnovel therapeuticspharmacologicpreconditioningpromoterprotein degradationreconstitutionsmall hairpin RNAsmall moleculesmall molecule therapeuticssymptomatologytemporal measurementtherapeutic targettoolubiquitin-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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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STUART H ORKIN其他文献
STUART H ORKIN的其他文献
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{{ truncateString('STUART H ORKIN', 18)}}的其他基金
Systems Biology Analysis of Human Erythropoiesis
人类红细胞生成的系统生物学分析
- 批准号:
9066186 - 财政年份:2014
- 资助金额:
$ 38.6万 - 项目类别:
Systems Biology Analysis of Human Erythropoiesis
人类红细胞生成的系统生物学分析
- 批准号:
9294127 - 财政年份:2014
- 资助金额:
$ 38.6万 - 项目类别:
Systems Biology Analysis of Human Erythropoiesis
人类红细胞生成的系统生物学分析
- 批准号:
8734667 - 财政年份:2014
- 资助金额:
$ 38.6万 - 项目类别:
Systems Biology Analysis of Human Erythropoiesis
人类红细胞生成的系统生物学分析
- 批准号:
8919832 - 财政年份:2014
- 资助金额:
$ 38.6万 - 项目类别:
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