HLS13-04 High-Content High-Throughput Screen for Diamond Blackfan Anemia Treatments

HLS13-04 用于 Diamond Blackfan 贫血治疗的高内涵高通量筛选

• 批准号: 8902889
• 负责人: Christopher Gibson
• 金额: $ 21.74万
• 依托单位: RECURSION PHARMACEUTICALS, LLC
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-15 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8902889
• 关键词: A549; Accounting; Algorithms; Anemia; Animal Model; Bioinformatics; Biological Assay; Biological Markers; CD34 gene; Cavernous Malformation; Cell Culture Techniques; Cell Death; Cell Line; Cells; Cerebrum; Chemicals; Clinic; Clinical Research; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; Computer software; Detection; Development; Diamond-Blackfan anemia; Disease; Disease model; Epithelial Cells; Erythrocytes; Erythropoiesis; Genes; Goals; Grant; Hereditary Disease; Human; Hydrops Fetalis; Image; Image Analysis; Immunofluorescence Immunologic; Individual; Inherited; Knock-out; Lead; Libraries; Life Expectancy; Machine Learning; Malignant Neoplasms; Measurement; Mediation; Mendelian disorder; Modeling; Mus; Mutation; Orphan Drugs; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phase I Clinical Trials; Phenotype; Population; Preclinical Drug Evaluation; Predisposition; Preparation; RNA Interference; Rare Diseases; Ribosomal Proteins; Severities; Small Business Innovation Research Grant; Small Interfering RNA; Stem cells; Stroke; Structural defect; Suspension substance; Suspensions; Symptoms; Syndrome; System; Technology; Testing; Therapeutic; Validation; Veins; Yeasts; base; bone marrow failure syndrome; cell type; disease phenotype; drug candidate; drug discovery; early onset; erythroid differentiation; experience; high throughput screening; knock-down; loss of function; new technology; phase 2 study; pre-clinical; preclinical study; public health relevance; sarcoma; screening; success; targeted treatment; tool; working group

 DESCRIPTION (provided by applicant): There are thousands of rare genetic diseases that have no approved treatment. Recursion Pharmaceuticals has developed a drug discovery platform that seeks to re-purpose known drugs for the treatment of such diseases. The platform consists of high content immunofluorescent image analysis using machine-learning algorithms to identify relevant and on-target changes induced by both RNAi and various chemicals. This system has been used to identify a phenotype for loss of function of two related genes, RPS19 and RPS10 in multiple human cell types. Mutations in these genes are the primary cause of Diamond Blackfan Anemia, a rare genetic disease with no specific targeted therapy. In this grant, we propose to: develop RPS19 and RPS10 knockout cell lines using CRISPR/Cas9 technology; evaluate knockout cell lines for phenotypes ('phenoprints') using our drug discovery platform; conduct chemical suppressor screens of thousands of known drug candidates to identify those that ameliorate on-target phenoprints associated with loss of RPS19 and RPS10; expand the capabilities of our drug screening platform to enable the use of non-adherent cell lines in our workflow and use the expanded capabilities to confirm the validity of drugs identifie as candidate therapies in CD34+ suspended cell culture models of Diamond Blackfan Anemia. Recursion Pharmaceuticals has the experience, tools, and drive to execute this Phase I SBIR proposal, and to accelerate commercial development of any compounds arising from the project. The proposed study would have significant societal and commercial implications.

 描述（由适用提供）：有成千上万种没有批准治疗的罕见遗传疾病。递归制药已经开发了一个药物发现平台，该平台试图重新使用已知药物治疗此类疾病。该平台由使用机器学习算法的高含量免疫荧光图像分析组成，以识别RNAi和各种化学品引起的相关和靶向变化。该系统已用于识别多种人类细胞类型中两个相关基因RPS19和RPS10功能丧失的表型。这些基因的突变是钻石黑针贫血的主要原因，这是一种罕见的遗传疾病，没有特定的靶向治疗。在这笔赠款中，我们建议：使用CRISPR/CAS9技术开发RPS19和RPS10敲除细胞系；使用我们的药物发现平台评估表型（'苯丙胺）的基因敲除细胞系；进行数千名已知药物的化学抑制筛查，以识别那些与RPS19和RPS10损失相关的靶向苯酚的筛选；扩展我们的药物筛查平台的功能，以便在工作流程中使用非辅助细胞系，并利用扩展的功能来确认药物的有效性确定为CD34+钻石黑芬贫血的悬浮细胞培养模型中的候选疗法。递归制药具有执行I阶段SBIR提案的经验，工具和动力，并加速了该项目引起的任何化合物的商业开发。拟议的研究将具有重大的社会和商业意义。