Researchers find drug that may suppress genetic mutation using a novel screening approach

"Currently most drugs are designed to act on a specific protein, but for most diseases we still don't know what the protein targets should be," says Randall Peterson, PhD, of the MGH CVRC, the paper's lead author. "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."

The researchers started with embryos of zebrafish – a tiny tropical fish used as a model of vertebrate development – with a mutation called gridlock, which prevents the correct development of the circulatory system in the lower portion of the body. A panel of these embryos was exposed to a very diverse library of small molecules – 5,000 in all – to see if any would prevent expression of the gridlock mutation. Two similar molecules were identified that suppressed the mutation, allowing the embryos to develop normally. The one that appeared more powerful, called GS4012, was chosen for further study.

The gridlock-suppressing effects of GS4012 were found to vary with dosage, and no vascular abnormalities were seen at the doses studied. Application of the compound appeared to be most effective at a developmental stage right before and during the formation of major vascular structures. Further experiments showed that GS4012 appears to promote the activity of the angiogenesis factor VEGF and also induces the development of vascular networks in cultured human vascular cells.

"We had a strain of fish with a very specific arterial defect, and although we knew which gene was responsible, there was a lot we didn't know about the molecular processes disrupted by that mutation," says Peterson "We were able to find a compound that could reverse the mutation and are hopeful that it will provide fundamental new insights into vascular development and disease.

"While this molecule may eventually have clinical application in promoting vascular growth after heart attack, stroke or injury, this new way of identifying potential new drugs may have an even greater impact," he adds. In addition to further studying the mechanism behind the action of the gridlock suppressors they identified, the research team hopes to apply this new drug-discovery approach to other diseases.

Massachusetts General Hospital, established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $400 million and major research centers in AIDS, cardiovascular research, cancer, cutaneous biology, medical imaging, neurodegenerative disorders, transplantation biology and photomedicine. In 1994, MGH and Brigham and Women's Hospital joined to form Partners HealthCare System, an integrated health care delivery system comprising the two academic medical centers, specialty and community hospitals, a network of physician groups, and nonacute and home health services.