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Abstract

Abstract: Phase I research developed a rapid, predictive assay for developmental organ toxicity testing using transparent zebrafish embryos. For the compounds tested, the Median Lethal Concentration (LC50) obtained using the zebrafish model correlated well with results from mammalian models. Using subtractive library techniques, Phase I studies also identified new zebrafish genes and pathways involved in organ toxicity response. These genes exhibit high protein sequence homology with their mammalian counterparts, suggesting that zebrafish embryo toxicity testing has a predictive value for mammals. Phase II research will further assess the predictive value of the zebrafish model by evaluating additional compounds, including potential anti-cancer therapeutics, whose toxicity effects have been characterized in mammalian models. Phase II research will also identify additional organ specific zebrafish genes involved in drug toxicity response and analyze changes in gene expression after drug exposure. These studies will result in a comprehensive set of genes that can eventually be used in a zebrafish cDNA microarray for drug screening and toxicity testing. PROPOSED COMMERCIAL APPLICATIONS: By providing a simple, rapid method for toxicity testing and drug screening, the proposed zebrafish-based assay will speed up the drug development process. The toxicity testing and drug screening markets are estimated at $500M and $700M, respectively.

Thesaurus Terms:
cytotoxicity, drug adverse effect, drug screening /evaluation, gene expression, method development, pharmacokinetics
DNA damage, embryo /fetus toxicology
microarray technology, northern blotting, nucleic acid sequence, subtraction hybridization, zebrafish

Institution:	PHYLONIX PHARMACEUTICALS, INC.
	100 INMAN ST, STE 300
	CAMBRIDGE, MA 02139
Fiscal Year:	2002
Department:
Project Start:	10-APR-2000
Project End:	30-SEP-2002
ICD:	NATIONAL CANCER INSTITUTE
IRG:	ZRG1