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

 描述（由申请人提供）：有数千种罕见的遗传性疾病没有批准的治疗方法。Recursion Pharmaceuticals开发了一个药物发现平台，旨在重新利用已知药物治疗此类疾病。该平台包括使用机器学习算法的高内容免疫荧光图像分析，以识别由RNAi和各种化学物质诱导的相关和靶向变化。该系统已用于鉴定多种人类细胞类型中两种相关基因RPS 19和RPS 10功能丧失的表型。这些基因的突变是Diamond Blackfan贫血的主要原因，这是一种罕见的遗传性疾病，没有特定的靶向治疗。在这项资助中，我们计划：使用CRISPR/Cas9技术开发RPS 19和RPS 10敲除细胞系;评估敲除细胞系的表型对数千种已知候选药物进行化学抑制剂筛选，以鉴定那些改善与RPS 19和RPS 10丢失相关的靶向表型的药物;扩大我们的药物筛选平台的功能，使非贴壁细胞系能够在我们的工作流程中使用，并使用扩展的功能来确认在Diamond Blackfan贫血的CD 34+悬浮细胞培养模型中确定为候选疗法的药物的有效性。Recursion Pharmaceuticals拥有执行第一阶段SBIR提案的经验、工具和动力，并加速该项目产生的任何化合物的商业开发。拟议的研究将产生重大的社会和商业影响。

 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.