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.
Public Health Relevance Statement: Public Health Relevance: There are thousands of rare genetic diseases that together affect millions of Americans. We will use chemical suppressor screens of known drugs, based on structural and functional changes in cellular disease models, to identify potential therapeutics for treatment of these diseases.
Project Terms: Affect; Algorithms; American; Animal Disease Models; Animal Model; base; Biological Assay; Candidate Disease Gene; Cavernous Malformation; Cell Line; Cell model; cell type; Cells; Cerebrum; Chemicals; Clinical Data; Clinical Trials; clinically relevant; Clustered Regularly Interspaced Short Palindromic Repeats; Collaborations; commercialization; cost; Data; direct application; Disease; Disease model; drug candidate; drug development; drug discovery; drug efficacy; Endothelial Cells; Epithelial Cells; Funding; Genes; genetic manipulation; Grant; Hereditary Disease; Human; human disease; Image; Image Analysis; Immunofluorescence Immunologic; In Vitro; Inherited; knock-down; Knock-out; Legal patent; Libraries; loss of function; loss of function mutation; Machine Learning; Marketing; Measurement; Mediation; Methods; Modeling; Mus; novel strategies; Orphan; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phase II Clinical Trials; Phenotype; Population; pre-clinical; Preclinical Drug Evaluation; Prevalence; Process; public health relevance; Rare Diseases; Research; Resistance; RNA Interference; Safety; screening; Small Business Innovation Research Grant; Small Interfering RNA; Source; stroke; success; Syndrome; Techniques; Technology; Therapeutic; Time
