An internal diagram of the eye reveals the structure of this complex organ. (Created by Ignacio Icke; via Wikimedia Commons.)
A new way to treat age-related macular degeneration, a leading cause of irreversible vision loss and impairment, may be on the horizon for the 11 million Americans suffering from the disease. Researchers at Indiana University School of Medicine have published a new study in the Journal of Pharmacology and Experimental Therapeutics showing how newly designed compounds can block the molecular mechanisms contributing to the disease–and perhaps offer a superior method to deliver treatments.
Tim Corson, PhD.
Tim Corson, PhD, from the Eugene and Marilyn Glick Eye Institute at the Department of Ophthalmology , and Mark Kelley, PhD, from the Wells Center for Pediatric Research at the Department of Pediatrics, have teamed up to explore different ways to treat wet age-related macular degeneration (wet AMD).
One of two forms of age-related macular degeneration, wet AMD accounts for 10 percent of macular degeneration cases but leads to 90 percent of legal blindness. The condition is characterized by irreversible damage to the macula in the retina, which is responsible for fine detail in the center of our vision as necessary for reading, driving and other daily activities. Wet AMD develops when the abnormal growth of blood vessels under the macula inappropriately distorts the shape of the macula, consequently distorting vision.
Mark Kelley, PhD.
“We set out to find new ways to target the abnormal blood vessel growth that we see with wet age-related macular degeneration,” said Corson, associate professor of ophthalmology. “Previous work had shown that a particular protein, called Ref-1, is important for blood vessel growth, or angiogenesis. We wanted to explore whether we could block angiogenesis with new derivatives of a drug, developed by Dr. Kelley and his company Apexian Pharmaceuticals, which targets Ref-1, as a first step toward developing new therapies.”
Ref-1 serves as a “signaling nexus” that mediates multiple pathways of proteins involved in blood vessel growth, Corson said. The protein can activate other proteins, known as transcription factors, which turn genes on or off during the development of blood vessels in the eye. If Ref-1 activates those transcription factors, abnormal blood vessel growth can occur. But by inhibiting Ref-1, those problematic downstream genetic processes are likewise inhibited, helping prevent or stop eye diseases like wet AMD. The synthesized compounds in the study did just that.
“We found these compounds worked really well to control Ref-1 and in turn control blood vessel growth in cell cultures and animal models,” Corson said. “With many other therapies, you can knock down one pathway contributing to the disease but another springs up, like a game of whack-a-mole. But with our Ref-1 targeting, we’re potentially whacking more moles at once. Another really exciting aspect is that while existing drugs must be injected into the eye, our compound can be delivered systemically, raising the possibility of an oral therapy.”
Corson and Kelley hope their findings may also be useful for other retinal diseases characterized by abnormal blood vessel growth, such as diabetic macular edema, diabetic retinopathy and retinopathy of prematurity. Additional studies will be needed, Corson said, to further explore Ref-1 and angiogenesis before therapies can be developed. Both researchers look forward to continuing their collaborative partnership.
“Collaboration is what drives science today. Bringing people together from related but sufficiently distinct disciplines brings new perspectives, new ideas, and new techniques can make important studies like this happen,” Corson said. “It’s great to work with a scientist who has different ideas and different expertise. What began as a side project has become an important part of what we’re doing in our lab.”
Indeed, the researching duo – and their new study – provide an excellent example of how important new discoveries can be made by combining efforts. While Corson studies mechanisms and potential therapies for conditions caused by abnormal blood vessel growth, Kelley is a world-renowned expert on Ref-1 and Chief Scientific Officer and Founder of Apexian Pharmaceuticals which provided the compounds used in the study. Their combined expertise and resources “really have pushed this study forward,” Corson said.
“This partnership between the Wells Center for Pediatric Research and the Glick Eye Institute is one example of the many collaborations that happen at IU School of Medicine every day,” Kelley said. “The unique resources and dynamic culture within the institution allow us to pursue our ultimate goal: to help patients.”
The views expressed in this content represent the perspective and opinions of the author and may or may not represent the position of Indiana University School of Medicine.
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