SBIR-STTR Award

Due to the high failure rates, drug development is a very expensive and inefficient process. Few of the millions of compounds generated by chemists are suitable for human use because of their toxicity. There is a major need to reduce the number of animals used in research while increasing the efficiency and reducing the costs of identifying safe and effective drugs. This proposal will support the development and validation of murine stem cell biology used in combination with gene and protein array technologies as a more predictive and cost effective in vitro test for toxic drugs and compounds. Known teratogens or toxins for adult organs (liver, heart, & nervous system) will be evaluated for their effects on the in vitro growth and development of the stem cell-derived tissues. Developing and validating the combination of in-depth protein and gene profiling with the broad clinically relevant biology represented during the in vitro differentiation of stem cells should enable the development of a powerful test system for identifying and recognizing important surrogate markers of human toxicity. The result will be a commercial screening system that will increase the efficiency and reduce the costs of drug development. PROPOSED COMMERCIAL APPLICATIONS: There is a very pressing need in the pharmaceutical industry for technology that increases the efficiency of prioritizing drug leads. Because the costs of development are so expensive and time consuming, working on a drug that will ultimately fail is enormously expensive. The proposed screening system should allow predictive toxicology assessment early during drug development and will be provided to the pharmaceutical industry as a screening service.

Development of new and improved drugs to treat human illness is a costly and inefficient process. It costs over half a billion dollars to develop a compound into a medicine and more than 90% of compounds that enter human clinical trials fail usually due to unexpected toxicity. The attrition rate is even higher at the preclinical level where less than 1 in 10,000 drug "hits" successfully makes it to FDA approval. VistaGen, Inc. is developing a simple and reproducible screening technology for in vitro toxicity assessment, the Genesis ScreenTM. The system employs stem cells capable of differentiating into most tissues in the body. Once the cells are exposed to test compounds, toxicity is evaluated as changes in genomic and proteomic expression patterns as measured using cDNA microarrays and a protein SELDI-TOF microchip technology. This assay can rapidly prioritize drug "hits" based on a straightforward in vitro safety assessment. The objective of our previously funded phase I SBIR was to provide proof of principle of the Genesis Screen TM technology. We have successfully completed the goals of our phase I grant and in particular made major progress in developing proteomic fingerprints of toxic drugs. Furthermore, we have started to develop the biomathematics that will allow us to statistically compare the profiles of our library of molecular fingerprints of reference toxic drugs to test compounds to predict whether those test compounds are likely to be toxic or not. The objective of our Phase II application is to refine our assay to the point of bringing the Genesis ScreenTM system to the full-scale commercialization stage. We propose studies to increase the resolving power of our proteomic and genomic surrogate markers for selective classes of compounds with known toxicity. We will further develop the biomathematics component of the Genesis ScreenTM system These development studies will allow us to commercialize to the pharmaceutical industry a rapid and reliable high throughput Genesis ScreenTM system assay for prioritizing drug lead candidates based on toxicity assessment.

Thesaurus Terms:
drug adverse effect, drug screening /evaluation, microarray technology, stem cell, technology /technique development, tissue /cell culture, toxicology antineoplastic, cell differentiation, gene expression, tissue /cell preparation animal tissue