Development of novel methods for toxicity assessment and drug discovery

BICHARA DB; SIMONETTA SH

Rosario

Congreso; Second Meeting of the Latin American Zebrafish Network (LAZEN); 2012

Universidad Nacional de Rosario / IBR

The standard process of drug development consists of in vitro biochemical and cell-based assays, followed by in vivo studies in animals and trials in humans. This takes 12- 15 years and costs millions of dollars, but less than 1% of developing drugs result in success. Much of the failure comes at the level of animal testing, where ADMET is first assessed. This could be overcome using in vivo animal models such as C.elegans and Zebrafish at the initial stage of this pipeline In our laboratory we are developing novel technologies for high-throughput screening using these models. First, we have developed an automatic device for measuring behavioral activity in zebrafish larvae. We determined the appropriate culture conditions, number of animals and stage of development to get robust results. Furthermore, we validated this methodology as a rapid toxicity test. By measuring the effects of reference compounds on larvae activity we were able to estimate the concentration that cause a 50% decrease in activity events values (AEC50), showing a strong linear correlation (W= 0.91) with the LC values obtained with the standard DarT test. In addition, we modified this device so now we can track the position, trajectory and speed of the larvae, in order to assess drugs which affect behavior or may produce convulsing effects. We are confident that this new in-vivo approach, combined with novel technologies, can help to discover new lead compounds, reducing time and saving money.