In this Phase II SBIR grant, we propose to develop our Phenotype MicroArray (PM) technology into a high throughput screening (HTS) assay for drug toxicity. The proposal addresses a key need in drug discovery for faster, simpler, and less expensive technologies that can assess drug candidates for potential toxicology as well as mechanism of action. Biolog has developed a prototype technology that can be employed for in vitro screening of drug toxicity. It is designed to work with human cell lines selected to represent the different organs and tissues where toxicity is typically exhibited. The 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 cultured 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. A unique aspect of this cell-based approach to toxicological testing is that we can see the effect of the drug on cells under nearly 2000 diverse physiological states of the cell. Alternative methods of testing cells or animals only test for toxicology in a healthy and proliferative state. Another unique aspect is that the technology also tests drug combinations and can provide highly useful synergy and antagonism information. In Phase II of this project we propose to expand the set of PM tests that can be performed from the current set of 600 to approximately 2000, miniaturize and automate the technology, and then construct an initial database of chemical fingerprints by testing 2000 chemicals of known classes and toxicities. In addition to applications in toxicology, this technology will be useful in basic research to study cell biology, metabolic diseases, and gene function, and in applied cell biology for QC testing of cell lines and bioprocess development.
| Bochner, Barry R; Siri, Mark; Huang, Richard H et al. (2011) Assay of the multiple energy-producing pathways of mammalian cells. PLoS One 6:e18147 |
