Expansion of an efficient drug repurposing platform for rare genetic diseases.

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。该平台包括高含量的免疫荧光图像分析和跨细胞阻力测量。这些测量使用机器学习算法进行评估，以识别由RNAi和各种化学品诱导的相关和靶向变化。这些检测可以同时在数千种罕见遗传疾病模型上进行。在这项资助中，我们特别提出：使用RNAi技术在多种人类细胞类型中模拟2,000种遗传疾病。 根据多参数量化，确定并优先考虑200个具有最引人注目的表型变化的疾病模型。 利用这200种疾病模型作为数千种已知候选药物的化学抑制剂筛选的基础。 在人类细胞中使用正交遗传操作技术筛选20种最佳药物/疾病组合。 在相关动物模型中研究最好的五到十种经过验证的药物/疾病组合。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 and transcellular resistance measurements. These measurements evaluated using machine-learning algorithms to identify relevant and on- target changes induced by both RNAi and various chemicals. These assays can be simultaneously performed on thousands of rare genetic disease models. In this grant, we specifically propose to: Model 2,000 genetic diseases in multiple human cell types using RNAi technology. Identify and prioritize 200 of these disease models with the most compelling phenotypic changes, according to multi-parametric quantification. Utilize these 200 disease models as the basis of chemical suppressor screens of thousands of known drug candidates. Validate the 20 best drug/disease combinations using an orthogonal genetic manipulation technique in human cells. Study the best five to ten validated drug/disease combinations in relevant animal models. The proposed study would have significant societal and commercial implications.