New Blood Vessel Growth Prevented in Mice with Wet AMD
This research was supported by BrightFocus
There’s been a major discovery from Washington University in St. Louis (WUSTL). In mice studies, researchers have shown that fibroblast growth factor (FGF) proteins, a family of "signaling proteins" involved in tissue formation, can be independently manipulated to bring about desired results in individual organs without disrupting the organism as a whole.
Funded in part by a grant from BrightFocus Foundation, this breakthrough represents a collaboration between the lab of 2010-13 BrightFocus Grantee Rajendra Apte, MD, PhD, professor of ophthalmology and visual sciences, and David M. Ornitz, MD, PhD, professor of developmental biology. They are senior authors on a report published online in the prestigious Proceedings of the National Academy of Sciences (PNAS), August 19.
While limited to mice, the results are potentially good news for humans suffering from certain conditions, including wet macular degeneration and slow wound healing from diabetes. FGF proteins are involved in embryonic development and also are critical players in blood vessel formation and wound healing. When an organ is injured, the healing process triggers blood vessel formation (angiogenesis) to nourish and regrow tissue at the injury site. With poorly controlled diabetes, healing can be compromised, and slow healing in some wounds, such as foot ulcers, leads to amputation.
What the Apte and Ornitz labs were able to show, collaboratively was that, on one hand, upping FGF improved wound healing in mice models of diabetes, while on the other hand, inhibiting FGF helped prevent choroidal neovascularization (CNS), the out-of-control growth of fragile, leaky blood vessels that distort vision and damage the retina, which is seen in both diabetic retinopathy and “wet” forms of age-related macular degeneration (AMD). In the advanced, “wet” stage of AMD, it’s believed that the retina, too, is responding to inflammation and other factors it “reads” as injury by forming new blood vessels—but in this case, the vessel growth harms, rather than heals, the eye.
To carry out their role in angiogenesis, FGF proteins bind with specific receptor molecules, FGFRs, located on the surface of many cell types. In their mice experiments, rather than to completely shut down FGFRs, Apte and Ornitz selectively manipulated their expression for two specific FGF proteins involved in formation of cells that line the interior of blood vessels and create new vasculature. Research had already suggested that these FGF pathways are not involved with normal development and tissue maintenance, and thus that healthy tissue would not likely be affected.
The results showed that to be true. Mice engineered to lack the targeted receptors were shown, once injured, to have fewer blood vessels surrounding the injury site and to heal more slowly than their normal littermates. In other respects, including longevity, they were normal.
“That’s an important point,” Dr. Apte was quoted in a WUSTL press release. “With any targeted therapy, we worry about damaging the normal vessels. But our work suggests that inhibiting FGF signaling in the eye may prevent this abnormal response without harming normal vessels.”
Ongoing plans call for the Apte lab to forge connections between this latest discovery and their ongoing investigation of the role that macrophage cells play in AMD—results were published by him and two members of his lab, Abdoulaye Sene, PhD (first author), and Rae Nakamura, PhD, in Cell Metabolism last year (2013), and summarized in our News Update. Sene and Nakamura are also coauthors on the PNAS report.
Wet macular degeneration (AMD) is usually preceded by the dry form of the disease. As the dry form worsens, abnormal blood vessels sometimes grow behind the macula. These vessels are fragile and will leak fluid and blood (hence the term “wet” macular degeneration). This accumulation of fluids lifts the macula, which distorts vision and causes damage to the macula. In wet AMD, straight lines may appear wavy, and central vision loss can occur rapidly. Straight-ahead vision can become distorted or lost entirely in a short period of time—sometimes within days.
A family of "signaling proteins" involved in tissue formation. Some are involved in angiogenesis (the growth of new blood vessels).
Choroidal neovascularization is the out-of-control growth of fragile, leaky blood vessels that distort vision and damage the retina, which is seen in both diabetic retinopathy and the “wet” form of age-related macular degeneration (AMD).
Angiogenesis is the growth of new blood vessels in the body.