Targeting Enzymatic Regulation of Fetal Hemoglobin Repression

胎儿血红蛋白抑制的靶向酶调节

• 批准号: 10627766
• 负责人: James Douglas Engel
• 金额: $ 215.78万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10627766
• 关键词: Adult; Affect; Animal Model; Biochemical; Biochemistry; Bone Marrow; CHD4 gene; Cell Culture Techniques; Cells; Cellular biology; Cessation of life; Childhood; Chromatin; Chronic; Clinical; Clinical Research; Clinical Trials; DNA Binding; DNA Modification Methylases; Development; Disease; Enhancers; Enzyme Inhibition; Enzyme Repression; Enzymes; Epigenetic Process; Erythroid; Erythroid Progenitor Cells; Evolution; Excision; Fetal Hemoglobin; Functional disorder; Future; Gene Expression; Genes; Genetic Diseases; Genetic Polymorphism; Genetic Transcription; Goals; Hemoglobin concentration result; Hemoglobinopathies; Hemolytic Anemia; High Prevalence; Histone Deacetylase; Human; In Vitro; Individual; Inherited; KDM1A gene; Life; Locus Control Region; Longevity; Modeling; Modification; Molecular; Molecular Target; Morbidity - disease rate; Mus; Oral; Organ; Outcome; Outcomes Research; Pain; Papio; Pathologic; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Population; Preparation; Production; Refractory; Refractory Disease; Regulation; Repression; Research; Reticulocytosis; SMARCA5 gene; Safety; Sickle Cell Anemia; Stroke; Testing; Therapeutic; Time; Validation; Work; acute chest syndrome; beta Globin; clinically significant; cytotoxic; design; fetal; gamma Globin; gene repression; genetic corepressor; hydroxyurea; improved; in vivo; in vivo evaluation; infancy; inhibitor; innovation; insight; low income country; migration; model organism; mouse model; new therapeutic target; novel; pharmacologic; pre-clinical; preservation; progenitor; programs; research study; sickling inhibitor; small molecule; small molecule inhibitor; structural biology; targeted treatment

Overall Abstract: The ultimate goal of this research program is to provide safe, effective, accessible and durable disease modification for sickle cell anemia (SCD) that will improve multi-organ pathophysiology and reduce early death. Research studies support the premise that fetal hemoglobin is the most powerful natural inhibitor of sickle cell disease pathophysiology, and that inactivating fetal γ-globin (HBG) gene repression would be therapeutic in human patients. The goals of this proposal focus on the manipulation and specific targeting of the transcriptional regulatory machinery that represses HBG genes during development. These studies are devoted to the identification of new drug targets, the epigenetic enzyme components that comprise the repression machinery, that will lead to γ-globin activation in the normally silenced HBG genes in adult erythroid progenitor cells (Project 1), to the modeling, synthesis and development of safe, effective and exquisitely specific therapeutic compounds that will be validated in vitro and in vivo in sickle cell disease model mice (Projects 1 and 3), and for those leads that prove to be most efficacious, onward to detailed characterization in the optimal model for human hemoglobinopathies, the baboon (Project 2) in preparation for human clinical trials (Project 3). The projected impact for patients suffering from β-globinopathies is that these proposed HbF- inducing therapies will be sufficiently robust so as to counter the devastating complications of these diseases (stroke, acute chest syndrome and early death) with safety parameters that will permit universal access as well as life-long use.

总体摘要： 该研究计划的最终目标是提供安全、有效、可及且持久的疾病 对镰状细胞性贫血（SCD）的修改将改善多器官病理生理学并减少早期死亡。 研究支持这样的前提：胎儿血红蛋白是镰状细胞最强大的天然抑制剂 疾病病理生理学，并且灭活胎儿 γ-珠蛋白 (HBG) 基因抑制将在以下疾病中发挥治疗作用： 人类患者。该提案的目标侧重于操纵和具体针对 在发育过程中抑制 HBG 基因的转录调控机制。这些研究是 致力于识别新药物靶点，组成的表观遗传酶成分 抑制机制，这将导致成人红细胞中通常沉默的 HBG 基因中的 γ-珠蛋白激活 祖细胞（项目1），安全、有效、精致的建模、合成和开发 特定的治疗化合物将在镰状细胞病模型小鼠体内和体外进行验证 （项目 1 和 3），对于那些被证明是最有效的线索，继续进行详细的表征 人类血红蛋白病的最佳模型，狒狒（项目 2），为人类临床做准备 试验（项目 3）。对患有 β-球蛋白病的患者的预计影响是，这些提议的 HbF- 诱导疗法将足够强大，足以应对这些疾病的毁灭性并发症 （中风、急性胸部综合症和过早死亡）的安全参数也将允许普遍获得 作为终身使用。

项目成果

A pilot clinical trial of the cytidine deaminase inhibitor tetrahydrouridine combined with decitabine to target DNMT1 in advanced, chemorefractory pancreatic cancer.

胞苷脱氨酶抑制剂四氢尿苷联合地西他滨在晚期化疗难治性胰腺癌中靶向 DNMT1 的初步临床试验。

• 发表时间: 2020
• 期刊: American journal of cancer research
• 影响因子: 5.3
• 作者: Sohal,Davendra;Krishnamurthi,Smitha;Tohme,Rita;Gu,Xiaorong;Lindner,Daniel;Landowski,TerryH;Pink,John;Radivoyevitch,Tomas;Fada,Sherry;Lee,Zhenghong;Shepard,Dale;Khorana,Alok;Saunthararajah,Yogen
• 通讯作者: Saunthararajah,Yogen

Epigenetic activities in erythroid cell gene regulation.

• DOI: 10.1053/j.seminhematol.2020.11.007
• 发表时间: 2021-01
• 期刊: Seminars in hematology
• 影响因子: 3.6
• 作者: Wang Y;Yu L;Engel JD;Singh SA
• 通讯作者: Singh SA

A new target for fetal hemoglobin reactivation.

胎儿血红蛋白再激活的新目标。

• DOI: 10.3324/haematol.2019.230904
• 发表时间: 2019
• 期刊: Haematologica
• 影响因子: 10.1
• 作者: Rivers,Angela;Molokie,Robert;Lavelle,Donald
• 通讯作者: Lavelle,Donald

Epigenetic regulation of hemoglobin switching in non-human primates.

• DOI: 10.1053/j.seminhematol.2020.12.001
• 发表时间: 2021-01
• 期刊: Seminars in hematology
• 影响因子: 3.6
• 作者: Molokie R;DeSimone J;Lavelle D
• 通讯作者: Lavelle D

Combinatorial targeting of epigenome-modifying enzymes with decitabine and RN-1 synergistically increases HbF.

• DOI: 10.1182/bloodadvances.2022009558
• 发表时间: 2023-08-08
• 期刊: BLOOD ADVANCES
• 影响因子: 7.5
• 作者: Ibanez, Vinzon;Vaitkus, Kestis;Zhang, Xu;Ramasamy, Jagadeesh;Rivers, Angela E.;Saunthararajah, Yogen;Molokie, Robert;Lavelle, Donald
• 通讯作者: Lavelle, Donald