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CITED-2 Protein Tackles Hypoxic Response in the Retina

Scripps Research scientists publish a brand-new approach to tackling eye treatment.


Regardless of whether the causes of eye diseases are age-related or genetically-inherited, the phenomenon that links them all together is known as neovascularization. According to WebMD, this process causes abnormal blood vessels to grow, caused by a lack of blood supply in the retina. Neovascularization is influenced by many factors, from aging to diabetes, but it is the human body’s way of attempting to secure proper blood flow. A number of problems arise if these defective vessels bleed, including vision-impairing hemorrhages and scar tissue. As these vessels are incredibly fragile, continually producing these vessels potentially blocks fluid flow within the eye, and eventually leads to glaucoma, one of the leading causes of blindness.


Image: CITED-2 Protein interacting with the blood vessels in the retina

https://www.scripps.edu/news-and-events/press-room/2020/20201027-friedlander-retina.html


Historically, when it comes to drug production for eye disease, opthamologists have put more emphasis on treating diseases that block the VEGF protein, which promotes such vessel growth. Although these drugs have greatly improved the conditions of different patients, they have a success rate of only about 40% among patients and bring up a number of safety concerns. Thus, Scripps Research scientists have developed a new method which does not target the VEGF protein.


Co-senior authors, Rebecca Berlow, PhD, a scientist working in the Department of Integrative and Structural and Computational Biology, and Martin Friedlander, MD, PhD, professor in the Department of Molecular Medicine at Scripps Research, are the two masterminds behind this method. As of now, their VEGF-friendly approach has been tested on mice and has already been observed to have more benefits than the traditional approaches.


Hypoxia is defined as the lack of oxygen in tissues, and it can happen anywhere in the body. Once activated, HIF-1, the protein responsible for detecting this condition can result in an increased production of VEGF to wherever parts necessary in the eye. Berlow and Friedlander’s method takes advantage of the “hypoxic response,” and rather than targeting the VEGF protein, they introduce a protein known as CITED2. This protein is created by the HIF-1, but ironically, it functions as a regulator for HIF-1, being able to switch hypoxic genes on and off in case the response produced is too powerful.


In the investigation, researchers experimented on mice models that supposedly had retinal hypoxia and showed signs of neovascularization. These mice were kept for observation after being injected with a fragment of the CITED2 protein into the eye. In the models, it was determined that if the CITED-2 protein was unsuccessful, the destruction of healthy vessels would be observed. However, in result, they actually saw that the HIF-1 activity was lowered by the protein fragment, and later on, even began to see that in the retina, healthy capillaries started to grow.


“‘Most hypoxia-related retinal disorders, such as diabetic retinopathy, have extensive capillary loss in late stages of disease, leading to neuronal cell death and vision loss,’ Friedlander says. ‘No current treatment has any therapeutic benefit for this aspect of the disorder.’”


In the future, the Scripps researchers hope to improve their CITED-2 method in order to begin human clinical trials.


Sources:

https://www.sciencedaily.com/releases/2020/10/201027192408.htm

https://www.webmd.com/diabetes/qa/what-is-neovascularization

https://webmd.com/asthma/guide/hypoxia-hypoxemia


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