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From left, Clare Murphy, research assistant, Jijun Hao, Ph.D., and Charles Hong, M.D., Ph.D., with some of their favorite research subjects. (photo by Dana Johnson)

Zebrafish making waves as drug discovery tool

BY: LEIGH MACMILLAN

12/21/2007 - Fish embryos may seem an unlikely tool for investigators searching for new drug candidates. But a first-of-its-kind screen for birth defects in zebrafish — designed by Vanderbilt cardiologist Charles Hong, M.D., Ph.D. — has turned up a compound that may offer leads for anemia and bone-related diseases.

Hong, assistant professor of Medicine, knew that signaling pathways involved in early development also play roles in disease processes. And he reasoned that a good way to find drugs that interfere with these pathways would be to expose developing embryos to certain chemicals and then to examine the embryos for specific defects.

“A theme of our research has been to look for compounds that disrupt dorsoventral (back-to-front) patterning, with the idea that such compounds would be selective inhibitors of clinically important signaling pathways,” Hong said.

With colleagues at Harvard Medical School, where he was a junior faculty member before coming to Vanderbilt, Hong established what he terms a “chemical genetics” screen.

He exposed developing zebrafish to a library of thousands of different compounds and evaluated the embryos for changes in the dorsoventral body axis.

In Nature Chemical Biology, the investigators report the identification of a single compound they call “dorsomorphin” because it “dorsalized” the embryos — it made their back-side structures more prominent.

The effects of dorsomorphin mimicked certain genetic changes to the BMP (bone morphogenetic protein) signaling pathway, Hong said, so the researchers suspected that the compound might act as an inhibitor of BMP signaling.

Hong and colleagues were surprised to learn that they had discovered the first selective BMP inhibitor.

Because the receptors for BMP are very similar to their “cousin” receptors that respond to the growth factor TGF-beta, traditional drug discovery methods have so far failed to uncover a compound that could discriminate between the two.

Dorsomorphin does discriminate — it inhibits BMP receptor signaling, but not TGF-beta receptor signaling.

“By looking first at a phenotype — in this case body pattern — in a live animal, we're sort of turning drug discovery upside down,” Hong said.

“When we identify a compound that disrupts patterning, we know it's doing something selective inside a live animal. Then we work backwards to find the signaling pathway it's affecting.

“In the past few years, we've proven that zebrafish can be a very useful drug discovery tool.”

Hong and colleagues are exploring the potential clinical applications for a selective BMP inhibitor such as dorsomorphin.

Recent studies have suggested that BMP may participate in maintaining iron levels in the body. The investigators used dorsomorphin to explore this role for BMP in mice and discovered that their new inhibitor could increase iron levels in the blood.

“Using this novel drug, we've helped uncover a whole new iron metabolism axis,” Hong said.

The findings could be useful in treating anemia associated with chronic disease in cancer and heart failure patients. The current therapy for these patients is erythropoietin, which often fails to improve blood cell numbers.

“We believe that dorsomorphin targets the true pathophysiology of anemia of chronic disease,” Hong said.

The investigators are also interested in dorsomorphin's potential applications for bone-related disorders, such as inappropriate bone formation following joint injury or surgery and the rare genetic disorder fibrodysplasia ossificans progressiva (FOP), which immobilizes its sufferers by turning their soft tissue into bone.

“This work demonstrates the power of chemical genetics,” Hong said.

“In a single paper we go from a 'pie in the sky' idea to finding a drug for an important pathway and showing that this could be a useful therapy.”

Hong and colleagues at Vanderbilt are continuing their zebrafish-based chemical genetics screens to search for more selective dorsomorphin-like compounds as well as drug candidates that inhibit other developmental signaling pathways.

The research was supported by the National Institutes of Health.

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