SBIR-STTR Award

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.

Thesaurus Terms:
cellular respiration, chemical structure function, colorimetry, drug adverse effect, drug screening /evaluation, microarray technology, technology /technique development cell line, high throughput technology, phenotype, toxicology

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.

Thesaurus Terms:
cellular respiration, drug screening /evaluation, high throughput technology, microarray technology, technology /technique development, toxicant screening cancer information system, cell growth regulation, colorimetry, drug adverse effect, drug discovery /isolation, liver cell, metabolism, molecular biology information system, phenotype, tissue /cell culture, toxicology information system biotechnology, cell line