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

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 RPS and RPS 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 RPS and RPS knockout cell lines using CRISPR Cas technology evaluate knockout cell lines for phenotypes andapos phenoprintsandapos 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 RPS and RPS 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 CD 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 PUBLIC HEALTH RELEVANCE Diamond Blackfan Anemia DBA is a rare genetic disease for which no targeted therapy exists Loss of function in RPS and RPS or other ribosomal protein genes results in the disease We will use chemical suppressor screens of known drugs based on structural changes in cellular disease models to identify potential therapeutics for treatment of DBA