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.
Public Health Relevance Statement: Public Health Relevance: Diamond Blackfan Anemia (DBA) is a rare genetic disease for which no targeted therapy exists. Loss of function in RPS19 and RPS10, 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.
NIH Spending Category: Biotechnology; Genetics; Hematology; Orphan Drug; Pediatric; Rare Diseases
Project Terms: A549; Accounting; Algorithms; Anemia; Animal Model; base; Bioinformatics; Biological Assay; Biological Markers; bone marrow failure syndrome; Cavernous Malformation; CD34 gene; Cell Culture Techniques; Cell Death; Cell Line; cell type; Cells; Cerebrum; Chemicals; Clinic; Clinical Research; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; Computer software; Detection; Development; Diamond-Blackfan anemia; Disease; Disease model; disease phenotype; drug candidate; drug discovery; early onset; Epithelial Cells; Erythrocytes; erythroid differentiation; Erythropoiesis; experience; Genes; Goals; Grant; Hereditary Disease; high throughput screening; Human; Hydrops Fetalis; Image; Image Analysis; Immunofluorescence Immunologic; Individual; Inherited; knock-down; Knock-out; Lead; Libraries; Life Expectancy; loss of function; Machine Learning; Malignant Neoplasms; Measurement; Mediation; Mendelian disorder; Modeling; Mus; Mutation; new technology; Orphan Drugs; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phase; phase 2 study; Phase I Clinical Trials; Phenotype; Population; pre-clinical; Preclinical Drug Evaluation; preclinical study; Predisposition; Preparation; public health relevance; Rare Diseases; Ribosomal Proteins; RNA Interference; sarcoma; screening; Severities; Small Business Innovation Research Grant; Small Interfering RNA; Stem cells; stroke; Structural defect; success; Suspension substance; Suspensions; Symptoms; Syndrome; System; targeted treatment; Technology; Testing; Therapeutic; tool; Validation; Veins; working group; Yeasts
