Could 500,000 zebrafish lead to the discovery of treatments that prevent vision loss?
Jeff Mumm, Ph.D., a retinal researcher at Johns Hopkins University, thinks so. He’s devised an innovative test that uses the tiny fish for screening potential vision-saving compounds. His project is funded through the Foundation’s Translational Research Acceleration Program (TRAP), which was established in 2008 to expedite the advancement of potential retinal-disease therapies into human studies.
Zebrafish, a favorite of aquarium enthusiasts, offer several advantages as a retinal research tool. Among them is their ability to quickly regenerate photoreceptors and the accessibility of their eyes, which makes them easy to observe.
Perhaps the greatest benefit of the species is the extensive knowledge of their visual system gained from the groundbreaking genetic studies of Harvard’s John Dowling, Ph.D. The world-renowned retinal investigator is an original member of the Foundation’s Scientific Advisory Board.
“John Dowling is a real champion in extolling them as a model for retinal diseases,” says Dr. Mumm. “His group developed and screened several zebrafish mutants for visual function, which led to valuable insights into how the retina develops and functions.”
Dr. Mumm adds that screening drug compounds right off the bat in an animal model — as opposed to screening them first in cultured cells — is potentially a more efficient and effective approach for identifying the most promising treatment candidates.
His experiment involves placing young zebrafish — the size of a pinhead — into tiny wells. A chemical is then put into the water to induce the death of their rod photoreceptors. Compounds are also added to the water to see how well they prevent rod cell death. Because the fish’s rods have also been genetically programmed to produce a yellow-fluorescent protein, the research team will know which compounds are working best based on the amount of fluorescence produced. A lot of yellow will indicate that a promising compound is saving rods.
The investigators will screen 3,360 compounds, the majority of which have been previously approved by the U.S. Food and Drug Administration and/or other regulatory organizations for use in humans.
“This repurposing strategy has become hot in the field as a way to make the whole clinical trial process more efficient,” says Dr. Mumm. “If you get a hit on a compound that has been very well characterized and the toxicity has been worked out well, you are in a good position to more quickly get approval for it from the FDA.”
Dr. Mumm will test six different doses of each compound — a strategy he learned from Chris Austin, M.D., of the National Center for Advancing Translational Sciences — to confirm a compound’s vision-preserving effect.
“Because the screening systems are becoming so fast — we now use robotics — it has become more feasible to evaluate multiple concentrations,” explains Dr. Mumm. “Not only do we reduce the number of false positives and negatives, we get good dose-response curve data, which provides better validation that something really works.”
After the most promising therapy candidates are identified through zebrafish screening, Barb Röhrer, Ph.D., a TRAP-funded researcher at the Medical University of South Carolina and co-founder of MitoChem Therapeutics, will test them in mouse models of retinitis pigmentosa. Ultimately, the best compound will be considered for evaluation in a human study.
“Dr. Mumm not only impressed us with his ingenuity,” says Stephen Rose, Ph.D., chief research officer of the Foundation. “He’s shown that he’s very eager to leverage the expertise and knowledge of other scientists. That delights us.”
For information on other TRAP-related projects, see this overview.