Small Molecule Therapeutics for Sickle Cell Anemia

镰状细胞性贫血的小分子疗法

基本信息

批准号：
10601679
负责人：
DAVID R ARCHER
金额：
$ 54.72万
依托单位：
EMORY UNIVERSITY
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：
2023-02-15 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10601679
关键词：
Address Advanced Development Affect Affinity African Algorithms Amino Acid Substitution Antisickling Agents Biological Assay Blood Blood capillaries Bone Marrow Transplantation Cell membrane Cellular Morphology Cessation of life Chemicals Chronic Clinical Clinical Research Cytolysis Development Disease Dissociation Dose Drug Interactions Effectiveness Erythrocytes Evaluation Exhibits FDA approved Fetal Hemoglobin Future Genes Genetic Diseases Globin Goals Half-Life Hemoglobin Hemoglobin concentration result Hemolysis Hereditary Disease Human Hypoxia Image Individual Investigational Therapies Kidney Failure Laboratories Lead Libraries Life Expectancy Medical Membrane Methods Microscopy Modeling Monitor Morphology Mus Osmosis Oxygen Pathogenicity Pathway interactions Patients Peripheral Persons Pharmaceutical Chemistry Pharmaceutical Preparations Phase Phenotype Physiological Preclinical Testing Property Red Blood Cell Count Reticulocyte count Series Shapes Sickle Cell Sickle Cell Anemia Stroke Structure-Activity Relationship Technology Testing Therapeutic Tissues Transfusion Treatment outcome analog animal efficacy animal safety beta Globin cost cytotoxicity test detection assay drug candidate efficacy evaluation efficacy study gene therapy hemoglobin polymer high throughput screening high-throughput drug screening human subject improved improved outcome in silico in vivo innovation medication safety meter miniaturize mouse model novel novel therapeutics pre-clinical preclinical study premature prevent response safety assessment safety study scaffold screening sickling side effect small molecule small molecule therapeutics targeted agent tool vaso-occlusive crisis

Address Advanced Development Affect Affinity African Algorithms Amino Acid Substitution Antisickling Agents Biological Assay Blood Blood capillaries Bone Marrow Transplantation Cell membrane Cellular Morphology Cessation of life Chemicals Chronic Clinical Clinical Research Cytolysis Development Disease Dissociation Dose Drug Interactions Effectiveness Erythrocytes Evaluation Exhibits FDA approved Fetal Hemoglobin Future Genes Genetic Diseases Globin Goals Half-Life Hemoglobin Hemoglobin concentration result Hemolysis Hereditary Disease Human Hypoxia Image Individual Investigational Therapies Kidney Failure Laboratories Lead Libraries Life Expectancy Medical Membrane Methods Microscopy Modeling Monitor Morphology Mus Osmosis Oxygen Pathogenicity Pathway interactions Patients Peripheral Persons Pharmaceutical Chemistry Pharmaceutical Preparations Phase Phenotype Physiological Preclinical Testing Property Red Blood Cell Count Reticulocyte count Series Shapes Sickle Cell Sickle Cell Anemia Stroke Structure-Activity Relationship Technology Testing Therapeutic Tissues Transfusion Treatment outcome analog animal efficacy animal safety beta Globin cost cytotoxicity test detection assay drug candidate efficacy evaluation efficacy study gene therapy hemoglobin polymer high throughput screening high-throughput drug screening human subject improved improved outcome in silico in vivo innovation medication safety meter miniaturize mouse model novel novel therapeutics pre-clinical preclinical study premature prevent response safety assessment safety study scaffold screening sickling side effect small molecule small molecule therapeutics targeted agent tool vaso-occlusive crisis

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项目摘要

Project Summary Sickle Cell Disease (SCD) is a common genetic condition that affects approximately 100,000 people of African heritage in the US, and more than 4 million worldwide. The disease is caused by a single amino acid substitution in b-globin that promotes a rigid sickle shape phenotype of red blood cells (RBCs) and eventually leads to numerous clinical manifestations such as vaso-occlusive crises, hemolysis, peripheral tissue damage, renal insufficiency, and premature death. Various therapeutic approaches have been approved or are in development for SCD, including bone marrow transplantation, gene therapy, induction of fetal hemoglobin, and anti-sickling agents. Clinically approved therapies often have limited effectiveness, significant side effects, or are too costly to reach the majority of SCD patients. Treatment of SCD would be advanced by development of novel and effective anti-sickling drugs. Our laboratory has developed an innovative imaging assay utilizing automated microscopy and customized algorithms that detect the sickled phenotype of RBCs. This assay has been miniaturized to the 1536-well plate format suitable for high throughput screening. Unlike previous approaches to identifying anti-sickling compounds – which are often limited to drugs that interact directly with hemoglobin – the new assay detects morphological changes in RBCs at very high throughput and provides identification of anti- sickling agents targeting pathways modulating hemoglobin polymerization or RBC morphology, including mechanisms that do not involve direct interaction with hemoglobin. This allows elucidation of new classes of potential therapeutics for SCD, as well as novel tools for investigating the underlying mechanisms of hemoglobin polymerization and RBC sickling. The overall goal of the R61 phase of this proposal is to generate anti-sickling candidates for future pre-clinical and clinical studies. We will carry out large scale, high throughput drug screening to identify molecules that prevent sickling of diseased RBCs. The resulting hits will be verified in dose response and a series of secondary assays. Lead compounds will be selected based on physiologically acceptable changes of hemoglobin oxygen affinity and RBC membrane deformability. Further optimization will be carried out in the R33 phase by medicinal chemistry. As part of the R33, lead scaffolds will be synthesized and evaluated for anti-sickling potency, hemoglobin oxygen affinity, and improved RBC membrane deformability to identify agents best suited for animal safety and efficacy studies. Townes HbSS mice expressing human globin genes will be used to test short term lethality, efficacy of anti-sickling activity, RBC oxygen affinity, and RBC half- life in vivo. As the final deliverable of this proposal, 3 or more drug candidates that are safe and efficacious in the mouse model will be selected for future pre-clinical studies.

项目摘要镰状细胞病（SCD）是一种常见的遗传病，影响了大约100,000名非洲人在美国的遗产，全球超过400万。该疾病是由单个氨基酸取代引起的在促进红细胞（RBC）的僵硬的镰刀表型的B-珠蛋白中，最终导致众多临床表现，例如血管熟悉的危机，溶血，周围组织损伤，肾脏不足和过早死亡。已批准或正在开发各种治疗方法对于SCD，包括骨髓移植，基因疗法，胎儿血红蛋白的诱导和抗助攻代理商。临床认可的疗法通常具有有限的有效性，重大副作用或太昂贵到达大多数SCD患者。 SCD的处理将通过开发新颖和有效的抗易觉药。我们的实验室已经开发了一种使用自动化的创新成像测定法显微镜和定制算法，可检测RBC的谨慎表型。这个测定是小型化适用于适用于高吞吐量筛选的1536孔板格式。与以前的方法不同鉴定抗裂缝化合物（通常仅限于与血红蛋白直接相互作用的药物）新测定检测RBC的形态学变化很高，并提供了抗 - 靶向途径调节血红蛋白聚合或RBC形态的疾病剂，包括不涉及与血红蛋白直接相互作用的机制。这允许阐明新类 SCD的潜在疗法以及研究血红蛋白的潜在机制的新型工具聚合和RBC病。该提案的R61阶段的总体目标是产生反踢的未来临床前和临床研究的候选人。我们将进行大规模的高通量药物筛选以鉴定可防止患病RBC的分子。由此产生的命中将以剂量验证反应和一系列次要测定。铅化合物将根据物理选择血红蛋白氧亲和力和RBC膜缺陷性的可接受变化。进一步的优化将通过药物化学在R33阶段进行。作为R33的一部分，将合成铅支架并评估了抗溶作用，血红蛋白氧亲和力和改善的RBC膜可变形性确定最适合动物安全和效率研究的代理。 Townes HBSS小鼠表达人类环球基因将用于测试短期杀伤力，抗溶活性的效率，RBC氧亲和力和RBC半 - 生命在体内。作为该提案的最终交付，有3个或更多的候选毒品安全有效将选择小鼠模型进行未来的临床前研究。