As phenotypic screening makes a comeback in drug discovery, its major issue is drug target identification. There arent good generalizable approaches to do target identification for compounds of interest. Identifying how a new drug works at the molecular level is critical for improving it, which is often needed to give it the best chance of ultimately being both safe and effective in patients. In this proposal, we demonstrate a genome-wide CRISPRi/a screening process in human cells that readily identifies the molecular target(s) for drugs of interest. We present preliminary evidence it can also identify alternative targets for the disease indication for the drug as well as potential side effect targets. We demonstrate this screening process can be applied to drugs for diverse diseases. Thus, it has the potential to improve the number of drugs that make it through drug development pipelines that currently have high failure rates such as those for Alzheimers and diabetes. In the last two decades companies like Foundation Medicine have used genomics to make an increasing impact on disease diagnostics in the Healthcare industry. We propose to similarly use genomics to make an impact on the pharmaceutical industry creating a drug diagnostics market in the process.
Public Health Relevance Statement: PROJECT NARRATIVE Identifying how a new drug works at the molecular level is critical for refining it, which is often needed to give it the best chance of ultimately being safe and effective in patients. In this proposal we demonstrate a genetic screening process that can identify which genes are most important to how a drug works. Moreover, we propose this screening process is generalizable to drugs for diverse diseases, thus potentially improving the number of drugs that make it through R&D pipelines with high failure rates such as those for Alzheimers and diabetes.
Project Terms: Alzheimer's Disease; Antineoplastic Agents; base; Biochemical Genetics; Biological; Biological Assay; Biology; Businesses; Categories; Cations; Cell Line; Cell model; cell type; Cells; chronic myeloid leukemia cell; Clinic; Clustered Regularly Interspaced Short Palindromic Repeats; cost; cost effective; CRISPR interference; Diabetes Mellitus; Diagnostic; Digestion; Disease; drug development; drug discovery; Drug Industry; Drug Screening; Drug Targeting; Enzymes; Failure; Feedback; Fluphenazine; Foundations; Gene Expression; Genes; genetic approach; Genetic Screening; Genome; genome wide screen; genome-wide; Genomics; Glyburide; Healthcare Industry; Hepatocyte; Human; Human Resources; improved; in vivo; Industrialization; Industry Collaboration; interest; K-562; K562 Cells; Knowledge; Libraries; Liver; Liver diseases; Medicine; Metabolic; Modeling; Molecular; Molecular Mechanisms of Action; Molecular Target; Muscle; Muscle Cells; Neurons; novel therapeutics; Patients; Pharmaceutical Preparations; Phase; Phenothiazines; Phenotype; Phosphoric Monoester Hydrolases; Phosphorylation Site; Physiological; Preparation; preservation; Process; Production; Protocols documentation; Publishing; Reagent; research and development; restriction enzyme; screening; Services; side effect; success; Technology; Testing; Therapeutic; Threonine; Time; Traction; Trypsin; Ursidae Family; Vision; Work
