Some serious ophthalmic diseases, including age-related yellow spot degeneration and diabetic retinopathy, are characterized by abnormal growth of new branches of retinal blood vessels, which can lead to progressive vision loss. This phenomenon is called neovascularization.
Retinal neovascularization, which impairs vision, is usually a false attempt by the body to restore blood flow disrupted by aging, diabetes, high blood cholesterol or other factors.
When the small vessels supplying the retina become narrowed or fail, oxygen levels in the retina decrease. In response to this condition, called hypoxia, the HIF-1α protein triggers a complex “hypoxia response,” involving increased production of the VEGF protein to deliver more blood to the right areas. In principle, this is an adaptive and beneficial response. But chronic hypoxia leads to chronic overgrowth of abnormal new blood vessels, often leak and cause blindness.
Over the past few years, ophthalmologists have treated these conditions with drugs that block the VEGF protein responsible for stimulating the growth of new blood vessels. Although such drugs stabilize or improve the quality of vision in most patients, they do not help about 40% of them. Moreover, long-term blocking of VEGF, a growth factor essential to the health of many tissues, including the retina, can do more harm than good. Many cases of retinal neovascularization involve the loss of tiny blood vessels elsewhere in the retina, and blocking VEGF suppresses or prevents these vessels from growing again.
Several years ago, scientists at Scripps Research described the workings of another protein that naturally reduces the hypoxic response and thus may provide the basis for an alternative treatment strategy. The CITED2 protein is produced by HIF-1α as part of the hypoxic response and arguably functions as a “negative feedback” regulator that blocks the ability of HIF-1α to turn on hypoxia response genes, preventing it from becoming too strong or lasting too long.
In their new study, the scientists conducted tests in a mouse model of retinal hypoxia and neovascularization using a fragment of the CITED2 protein. They showed that it reduced the activity of genes that are normally turned on by HIF-1α in retinal cells and significantly reduced neovascularization. Moreover, it did so by preserving or allowing the re-growth of healthy capillaries in the retina that would otherwise be destroyed. In other words, CITED2 prevented vessel obliterations.
In the same mouse model, the researchers tested a drug called aflibercept, a standard treatment against VEGF. It helped reduce neovascularization but did not prevent the destruction of retinal capillaries. However, reducing the dose of aflibercept and combining it with the CITED2 fragment produced better results than either drug alone. Neovascularization was reduced while retinal capillaries were preserved and restored.
The researchers concluded that CITED2’s ability to combine these two benefits was a key achievement. They now hope to further develop a treatment based on CITED2 and test it in human clinical trials.
Photos by Shutterstock / FOTODOM UKRAINE
-
- Ayumi Usui-Ouchi, Edith Aguilar, Salome Murinello, Mitchell Prins, Marin L. Gantner, Peter E. Wright, Rebecca B. Berlow, Martin Friedlander. An allosteric peptide inhibitor of HIF-1α regulates hypoxia-induced retinal neovascularization. Proceedings of the National Academy of Sciences, 2020; 202017234 DOI: 10.1073/pnas.2017234117
