Zebrafish Model for Whole-Organism Drug Screening

A new method for identifying drug candidates for the treatment of diseases caused by genetic mutations does not require pinpointing the specific genes or proteins to be targeted.

Investigators at Massachusetts General Hospital (Boston, USA) utilized the zebrafish embryo model in this work. They studied embryos from a strain with the "gridlock” mutation, which prevents the correct development of the circulatory system in the lower portion of the body. More than 5,000 small molecules were screened for their ability to reverse the gridlock syndrome. As reported in the May 2004 issue of Nature Biotechnology, two molecules were found that suppressed the mutation, allowing the embryos to develop normally.

The more potent of the two compounds, GS4012, was further studied using human vascular cells growing in tissue culture. It was found that GS4012 promoted the activity of the angiogenesis factor VEGF (vascular endothelial growth factor) and also induced the development of vascular networks.

"Currently most drugs are designed to act on a specific protein, but for most diseases we still do not know what the protein targets should be,” explained first author Dr. Randall Peterson, a researcher in the Cardiovascular Research Center at Massachusetts General Hospital. "This is a totally different approach that shows how, without knowing the best target, you can screen for drugs that could reverse a disease and in the process learn something new about the underlying biology.”




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