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Distinguished Professor Koh Donates His Ho-Am Prize Money
(From left: Distinguished Professor Gou Young Koh and KAIST President Sung-Chul Shin) Distinguished Professor Gou Young Koh from the Graduate School of Medical Science and Engineering donated one hundred million KRW to KAIST that he received for winning the Ho-Am Prize. Professor Koh, who is widely renowned for angiogenesis, was appointed as the 2018 laureate of the 28th Ho-Am Prize for demonstrating the effective reduction of tumor progression and metastasis via tumor vessel normalization. He made the donation to the Graduate School of Medical Science and Engineering, where he conducted his research. “As a basic medical scientist, it is my great honor to receive this prize for the recognition of my research outcome. I will give impetus to research for continuous development,” Professor Koh said. Professor Koh also received the 5th Asan Award in Medicine in 2012 and the 7th Kyung-Ahm Award in 2011. He was also the awardee of the 17th Wunsch Medical Award. He has donated cash prizes to the school every time he is awarded. KAIST President Sung-Chul Shin said, “I would like to express my gratitude to the professor for his generous donation to the school. It will be a great help fostering outstanding medical scientists. Professor Koh received his MD-PhD from the Medical School of Chonbuk National University. After finishing his post-doctoral program at Cornell University and Indiana State University, he was appointed as a professor at Chonbuk National University and POSTECH. Currently, he holds the position of distinguished professor at KAIST and director of the IBS Center for Vascular Research.
Draining Eyes Clogged with Glaucoma
Professor Gou Young Koh in the Graduate School of Medical Science and Engineering and his team have identified a new mechanism involved in the development and progression of glaucoma, and found a potential therapeutic option to treat it. Glaucoma is the second cause of irreversible blindness, after cataracts. It affects about 3.5% of the world population aged 40 to 80. Professor Koh also serves as the director of the Center for Vascular Research at the Institute for Basic Science. The IBS said the study, published in the Journal of Clinical Investigation, is expected to help the development of therapies to treat primary open-angle glaucoma (POAG), which counts for three quarters of all glaucoma patients. One of the most important risk factors for glaucoma is the increased pressure inside the eye. A liquid called aqueous humor is constantly produced and drained out from the eye. It transports nutrients and inflates the eye giving it a roughly spherical shape. However, if this fluid cannot flow out of the eye chambers freely, an increase in intraocular pressure can damage the optic nerve, leading to vision loss. The precise mechanism of elevated resistance to aqueous humor outflow remains unclear, and although the current treatments for glaucoma tackle the production and outflow of aqueous humor, their outcomes are still poor. A component of the eye that plays a fundamental role in draining out the aqueous humor is Schlemm's canal. It collects the aqueous humor and mediates its transfer from the eye chambers to blood circulation. The cells on the walls of the canal, endothelial cells, ship the liquid from the inner to the outer side in “packages”, called vacuoles. As the shape and number of the vacuoles reflects the outflow performance, several giant vacuoles are expected in the normal outflow process. The team explained how imbalances in Schlemm's canal significantly increase the risk of glaucoma. They showed that an important regulator for canal functionality is the angiopoietin-Tie2 system. Angiopoietins, such as Ang1 and Ang2, are proteins important for the growth of new blood vessels and Tie2 is the receptor that binds them. It is known that the angiopoietin-Tie2 system plays a role in Schlemm’s canal formation, as Tie2 mutations or angiopoietin absence result in congenital glaucoma. However, this study clarified that it is also critically important during adulthood. The researchers reported that adult mice deficient in Tie2 suffer from an elevated intraocular pressure, retinal neuronal damage and partial visual impairment. Moreover, they had a markedly decreased number of giant vacuoles inside Schlemm’s canal endothelial cells, which indicate a poor aqueous humor drainage. The scientists also investigated if and how this process changes in older mice, as aging is a major risk factor for glaucoma, and showed that aged mice experience reduced levels of giant vacuoles, Tie2, Ang1, and Ang2, as well as other proteins connected with the angiopoietin-Tie2 pathway, like Prox1. To test whether Tie2 activation could shift the situation, the researchers tested the antibody ABTAA (Ang2-binding and Tie2-activating antibody). They injected it in one eye of mice, while the other eye of the same mice functioned as the negative control. After one week, levels of Tie2 and Prox1, number and diameter of giant vacuoles in Schlemm’s canals increased in the ABTAA-treated eyes compared to control eyes. The researchers observed a similar outcome with decreased intraocular pressure when ABTAA was injected to the eyes of mice suffering from POAG with regressed Schlemm’s canals, indicating that this antibody might be considered as a therapeutic option. "Slow development of glaucoma treatments is partly due to the poor understanding of the underlying pathogenesis," said Professor Koh, the corresponding author of the study. "We hope that identifying the critical role of the angiopoietin-Tie2 system in adult Schlemm’s canals will bring a significant boost in the development of therapeutics." Figure 1: Schlemm's canal position inside the eye. Schlemm's canal (green) plays a fundamental role in draining the aqueous humor (white arrows) from the anterior chamber of the eye to blood circulation. If the aqueous humor is not able to flow out freely, elevated intraocular pressure damages the optical nerve causing glaucoma and eventually blindness. Figure 2: Electron microscope images reveal how the aqueous humor is packaged in vacuoles (arrowheads) inside the cells forming the walls of Schlemm's canal. Aging and glaucoma cause the number and size of giant vacuoles to decrease, meaning that the aqueous humor outflow is compromised. The images compare the giant vacuoles in Schlemm's canals of a healthy mouse (top) and a mouse lacking Tie2 (bottom) Figure 3: The Ang2-binding and Tie2-activating antibody (ABTAA) rejuvenates the eye of aged mice and rescues them from glaucoma. Aging causes a reduction of the protein Tie2, a risk factor for increased intraocular pressure and glaucoma. In this experiment, one eye of mice lacking Ang1 and Ang2 was injected with the premixed ABTAA and Ang2, while the other eye was used as negative control. The researchers observed an increase in the area of Schlemm’s canal, together with higher levels of Tie2 (red) and lower intraocular pressure, suggesting that ABTAA restores the canal's functionality. The image includes the transcription factor Prox1 (green) and CD144 (blue), a protein present at the junctions between cells that form the wall of the canal. The angiopoietin-Tie2 system and Prox1 are linked by a vicious circle: the less Tie2 and Ang2, the less Prox1, leading to Schlemm's canal damage, increase in intraocular pressure, and acceleration of glaucoma progression.
The Antibody That Normalizes Tumor Vessels
Researchers also discover that their antisepsis antibody reduces glioma, lung and breast cancer progression in mice. A research team at the Center for Vascular Research within the Institute for Basic Science (IBS) discovered that the antisepsis antibody ABTAA (Ang2-Binding and Tie2-Activating Antibody) reduces tumor volume and improves the delivery of anti-cancer drugs. Published in Cancer Cell, this study demonstrates that ABTAA restores the structural and functional integrity of tumor blood vessels in three different tumor models: breast, lungs, and brain. Blood vessels inside and around an established tumor can be described as a chaotic and dysfunctional labyrinth. While the inner walls of healthy blood vessels are surrounded and supported by endothelial cells and other cells called pericytes, in the established tumor, the endothelial junctions are broken apart and pericytes are also detached. Blood flow into and from the tumor is severely retarded and tumor vessels lacking an intact vessel wall become leaky. This microenvironment causes limited drug delivery to the tumor and leads to inadequate oxygen supply (hypoxia) and even metastasis. The research team led by Professor Gou-Young Koh at KAIST’s Graduate School of Medical Science and Engineering found that the antibody ABTAA normalizes the tumor vessels and hence, change the whole tumor microenvironment. “We call it normalization of tumor vessels, because it resembles closely the wall architecture of healthy, normal vessels,” explains PARK Jin-Sung, first author of the study. And continues: “Tumor can adapt to hypoxia and get more aggressive, so we tried to prevent this transition by normalizing tumor vessels. ABTAA changes the whole tumor environment, oxygenation status and level of lactate, so that the immune cells and drugs can reach the core regions of the tumor more easily. In this way, we create a favorable ground for tumor treatment.” In an attempt to generate antibodies targeting the protein Ang2, which is specifically expressed by endothelial cells in stressful conditions like in tumor, the team unexpectedly discovered that ABTAA has a peculiar way of working and a dual function. ABTAA indeed not only blocks Ang2, but also activates Tie2 at the same time. Tie2 is a receptor present on the cell membrane of endothelial cells. ABTAA causes Ang2 to cluster together and to strongly activate Tie2 receptors. “If we activate Tie2, we can efficiently normalize tumor vessels, enhance drug delivery and change the whole microenvironment,” explains KOH Gou Young, Director of the Center for Vascular Research. Several pharmaceutical companies are developing Ang2-blocking antibodies to cure cancer. However, even if these antibodies significantly inhibit tumor progression, they do not stop tumor hypoxia. Moreover, most of the anti-cancer drugs target the tumor at its early stage, when tumors are still hard to diagnose. ABTAA, instead, works with tumors that are already rooted: “When the tumor is established, hypoxia is the main driver of tumor progression. So, if we eliminate hypoxia, we make the tumor milder, by reducing its progression and metastasis,” comments Koh. Figure: Schematic drawing of a blood vessel around tumors before and after treatment with ABTAA. The picture above shows a typical tumor vasculature characterized by damaged walls, red blood cells leakage and detached pericytes. Activating Tie2 on endothelial cells with the antibody ABTAA restores the normal vessel architecture: endothelial and pericytes on the vessel walls are stabilized, the delivery of blood is improved, and the anticancer drugs are more likely to reach the tumor core. The researchers tested ABTAA in mice with three different types of tumors that show high levels of Ang2: glioma (a type of a brain tumor), lung carcinoma, and breast cancer. They also compared the effect of ABTAA with ABA, another antibody that blocks Ang2 but misses the Tie2 activating properties. In all three cases, ABTAA was superior to ABA in inducing tumor vessel normalization, which led to a better delivery of the anti-cancer drugs into the tumor core region. Glioma is one of the so-called intractable diseases, because of its poor prognosis and treatment. Professor Koh’s team found that the glioma volume was reduced 39% by ABTAA and 17% by ABA. ABTAA profoundly reduced vascular leakage and edema formation in glioma through promoting vascular tightening. Moreover, when ABTAA was administered together with the chemotherapeutic drug temozolomide (TMZ), the tumor volume reduces further (76% by ABTAA+TMZ, 51% by ABA+TMZ, and 36% by TMZ). In the Lewis Lung Carcinoma (LLC) tumor model, the team administered ABTAA together with a chemotherapeutic drug called cisplatin (Cpt) and observed a greater suppression of tumor growth (52%) compared with the controls and increased overall survival. Moreover, ABTAA+Cpt led to a marked increase in necrotic area within tumors. Finally, in a spontaneous breast cancer model, ABTAA delayed tumor growth and enhanced the anti-tumor effect of Cpt. Courtesy of the Institute for Basic Sciences (IBS) Figure: The antibody ABTAA alone and in combination with other anti-cancer drugs have a beneficial effect in reducing tumor volume. ABTAA was tested in mice with brain tumor (glioma), lung or breast cancer. The image shows the improvements: reduction in glioma tumor size, reduction in metastatic colonies in lung tumor and decrease in necrotic regions in breast tumor. In the future, the team would like to further understand the underlying relationship between faulty blood vessels and diseases. “We would like to apply this antibody to an organ that is rich in blood vessels, that is the eye, and see if this antibody can be useful to treat eye diseases such as age-related macular degeneration and diabetic retinopathy,” concludes Koh. Professor Gou-Young Koh (left) and Jin-Sung Park (right)
The Journal of Clinical Investigation: Researchers Uncover the Secret Lymphatic Identity of the Schlemm's Canal
The Journal of Clinical Investigation (JCI), a peer-reviewed, top-tier medical journal published by the American Society for Clinical Investigation, carried a commentary entitled “Schlemm’s Canal: More Than Meets the Eye, Lymphatics in Disguise” in the July 25, 2014 issue. In the commentary, the authors compared a research paper (“Lymphatic regular PROX1 determines Schlemm’s canal integrity and identity”) by Professor Gou-Young Koh of the Graduate School of Medical Science and Engineering at KAIST with research work from the University of Helsinki (article entitled “The Schlemm’s canal is a VEGF-C/VEGFR-3 responsive lymphatic-like vessel”). The JCI released a press statement dated July 25, 2014 on its commentary. It mentioned that glaucoma, one of the leading causes of blindness worldwide, elevates eye pressure owing to poor drainage of aqueous humor. A specialized structure called “Schlemm’s canal” funnels aqueous humor from the eye back into circulation, which is critical to prevent pressure buildup in the eye. The article discussed the role of Schlemm’s canal in the context of lymphatic vascular characteristics by reviewing two research group’s papers back-to-back. For the full text of the press release, please visit the link below: Press Release from the Journal of Clinical Investigation, July 25, 2014 “Researchers uncover the secret lymphatic identity of the Schlemm’s canal” http://www.eurekalert.org/pub_releases/2014-07/joci-rut072414.php
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