Advancing fetal hemoglobin to the clinic using highly predictive in vivo strategies

使用高度预测的体内策略将胎儿血红蛋白推向临床

基本信息

批准号：
10400173
负责人：
DONALD LAVELLE
金额：
$ 45.42万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10400173
关键词：
Adult Adverse effects Animal Model BFU-E Blood - brain barrier anatomy Blood Platelets CHD4 gene Cell Count Cells Clinic Clinical Research Clinical Trials Collaborations Combined Modality Therapy Complex DNA Methyltransferase Inhibitor DNA Modification Methylases Decitabine Deoxygenated Sickle Hemoglobin Development Dose-Limiting Drug Combinations Drug Targeting Effectiveness Enzyme Inhibitor Drugs Enzymes Epigenetic Process Erythrocytes FDA approved Fetal Hemoglobin Food-Drug Interactions Future Gene Expression Regulation Gene Silencing Generations Genes Globin Goals Hematological Disease Hematology Hemoglobin F Disease Hemoglobin concentration result Histone Deacetylase Human In Vitro Individual Inherited KDM1A gene Laboratories Longevity Modeling Modification Niacinamide Oral Papio Patients Pharmaceutical Preparations Pharmacology Pharmacotherapy Phase Physiological Platelet Count measurement Population Pre-Clinical Model Primates Quality of life Reaction Refractory Regimen Regulation Repression Repressor Proteins Severities Sickle Cell Anemia Sickle Cell Trait Structure Symptoms Testing Tetrahydrouridine Therapeutic Therapeutic Index Toxic effect beta Thalassemia chromatin remodeling combinatorial design effective therapy erythroid differentiation first-in-human gamma Globin genetic corepressor hematopoietic differentiation hydroxyurea in vivo inhibitor innovation man mouse model neurotoxicity neutrophil novel novel therapeutics patient subsets polymerization promoter protective effect recruit side effect synergism therapy design translational potential

项目摘要

Project Summary Abstract Elevated fetal hemoglobin levels lessen the severity of sickle cell disease (SCD) and increase the lifespan of patients. Effective treatment of the large numbers of SCD patients projected in the U.S. and worldwide in the coming years would be best accomplished with an affordable, easily-administered, orally-available drug therapy designed to increase Fetal Hemoglobin (HbF) levels to a target >30% distributed throughout a large percentage of erythrocytes. Hydroxyurea (HU), currently the sole FDA-approved drug for SCD, is only effective in approximately 50% of patients and the HbF remains heterogeneously distributed among erythrocytes resulting in a large fraction lacking the protective effects of HbF. A logical approach to increase HbF that has been successfully pursued by our laboratory is to intervene with the epigenetic mechanism executing the switch from HbF to HbA expression in adults using pharmacological inhibitors of enzymes that catalyze repressive epigenetic modifications associated with γ-globin gene silencing. Our laboratory has developed and utilized an in vivo baboon model for over thirty years to investigate globin gene regulation and the in vivo activity of HbF-inducing drugs. Simian primates such as the baboon are widely acknowledged as the best animal models for testing the ability of new drugs to increase γ-globin expression because the activity of HbF-inducing agents is predictive of effects in man due to conservation of the structure and developmental stage-specific regulation of the β-like globin genes in simian primates. Initial studies from our laboratory demonstrating that DNA methyltransferase (DNMT) inhibitors increased HbF in baboons were followed by a number of clinical trials that confirmed their effectiveness in SCD patients and validated use of the baboon model. Recently we have shown that the LSD1 inhibitor RN-1 increased γ-globin expression in the sickle cell disease mouse model and in baboons and that long term treatment of baboons was well tolerated. In this proposal we will 1) investigate a combinatorial drug regimen targeting both DNMT1 and LSD1 for effects on HbF induction and reduction of potentially adverse hematological side-effects, 2) continue to advance new highly specific “third generation” LSD1 inhibitors with reduced ability to cross the blood brain barrier with the goal of increasing HbF to therapeutic levels, maximizing F cell numbers, and raising the therapeutic index, and 3) investigate new compounds that expand the BFU-E subpopulation permissive for γ-globin expression, alone and in combination with inhibitors of epigenetic-modifying enzymes, for additional stimulation of HbF induction. We envision that the results of these studies will directly impinge in the design of new clinical trials to increase HbF for the therapy of sickle cell disease. OMB No. 0925-0001/0002 (Rev. 03/16 Approved Through 10/31/2018) Page Continuation Format Page

项目摘要摘要胎儿血红蛋白升高镰状细胞病（SCD）的严重程度并增加了寿命在美国和全球投射的大量SCD患者的有效治疗未来几年最好通过负担得起的，易于管理的，可用的药物来完成旨在将胎儿血红蛋白（HBF）水平提高到靶标> 30％的治疗红细胞的百分比。在大约50％的HBF中生效仍存在异质分布红细胞导致大量缺乏HBF的保护作用。我们实验室成功追求的HBF是干预表观遗传机制使用药理学在成年人中执行从HBF到HBA表达的转换催化与γ-球蛋白基因沉默有关的抑制性表观遗传修饰开发并利用了三十三十三十三十三十三十三十的体内模型来研究球蛋白基因调节和 HBF诱导药物的体内活性。测试新药增加γ-珠蛋白表达能力的最佳动物模型，因为活性 HBF诱导剂的诱导剂可预测由于结构和发育的保存而导致人类的影响我们实验室的初始研究中β样球蛋白基因的特异性调节证明DNA甲基转移酶（DNMT）抑制剂在狒狒中增加了HBF的增加。确认其在SCD患者中的有效性并验证了狒狒的UFE的Clial数量最近，我们表明LSD1抑制剂RN-1在镰状细胞中增加疾病小鼠模型和狒狒以及狒狒的术语治疗良好。提案我们将1）研究针对DNMT1和LSD1的组合药物方案，以对 HBF指示和减少潜在的不良血液学副作用，2）继续推进新的高度特异性的“第三代” LSD1吸入器具有降低与血液屏障的能力降低的能力。将HBF提高到治疗水平，最大化F细胞数并提高治疗指数的目标 3）研究新的化合物，即BFU-E亚群允许γ-珠蛋白表达，单独使用并结合表观遗传修饰酶的吸入器，以供其他HBF指示站。我们设想了在新的Clials设计中直接影响研究的结果以增加 HBF治疗镰状细胞疾病。 OMB No. 0925-0001/0002（Rev. 03/16批准通过10/31/2018）页面延续格式页面