Phenotype MicroArrays for Drug Toxicity Screening

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DESCRIPTION (provided by applicant): Biolog has developed Phenotype MicroArrays (PMs) that can be employed as an in vitro screen for drug toxicity. This technology can measure thousands of physiological parameters of a cell in a simple-to-use HTS format. The core of the technology is a chemistry and image analysis system that detects changes in respiratory activity of cells grown under different physiological conditions. The changes in metabolic activity of the cell are measured as a colorimetric response detected with Biolog's automated OmniLog instrument. PMs allow for an information-rich colorimetric pattern to be generated for each drug and cell line examined. When a drug is tested in the PM, the colorimetric pattern changes and using pattern recognition technology, we can relate the color changes in the PM to the mode of action and side effects of the drug. The pattern is a fingerprint of that drug's action. When we test a large number of drugs with known pharmacological action, the individual fingerprints of each drug will have commonalities that will allow us to identify a reference standard for that class of pharmacological agents. A database of these signatures can be used to categorize novel compounds in a HTS program. Importantly, by testing drugs with well known in vivo toxicity, the fingerprints will have information about the toxicology of the drug tested and can be used to predict whether a drug "hit" will be toxic later on in development. In this Phase I SBIR grant, we propose to develop our PM technology into a HTS assay for drug toxicity. Two tissues which are most susceptible to drug toxicity are the liver and blood and these can serve as a good barometer for drug toxicity potential. In this grant we will optimize new prototype PMs and testing protocols for human liver and hematopoietic cell lines. We will then test a series of well-studied drugs that are structurally and mechanistically distinct but which have known toxicity and side effects in vivo. The profiles of metabolic activity generated by these drugs will be collated to generate a prototype of a database that can be used to screen small molecules for toxicity potential. In future studies (Phase II SBIR) we will expand the technology and scope of reference drugs tested to build a strong predictive database including cell lines representing more tissues and organs.