한빛사 논문
Jaeryung Kim1,2,3,*, Jang Ryul Park4,5,*, Jeongwoon Choi1,2, Intae Park1,2, Yoonha Hwang5,6, Hosung Bae1,2, Yongjoo Kim4,5, WooJhon Choi5, Jee Myung Yang2, Sangyeul Han1, Tae-Young Chung3, Pilhan Kim5,6, Yoshiaki Kubota7, Hellmut G. Augustin8,9, Wang-Yuhl Oh4,5,† and Gou Young Koh1,2,†
1 Center for Vascular Research, Institute for Basic Science (IBS), Daejeon 34141, Republic of Korea.
2 Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea.
3 Department of Ophthalmology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea.
4 Department of Mechanical Engineering, KAIST, Daejeon 34141, Republic of Korea.
5 KI for Health Science and Technology (KIHST), KAIST, Daejeon 34141, Republic of Korea.
6 Graduate School of Nanoscience and Technology, KAIST, Daejeon 34141, Republic of Korea.
7 The Laboratory of Vascular Biology, School of Medicine, Keio University, Tokyo 160-8582, Japan.
8 European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim 68167, Germany.
9 Division of Vascular Oncology and Metastasis, German Cancer Research Center, DKFZ-ZMBH Alliance, Heidelberg 69121, Germany.
*These authors contributed equally to this work.
† Corresponding author : Wang-Yuhl Oh, Gou Young Koh
Abstract
Choriocapillary loss is a major cause of neovascular age-related macular degeneration (NV-AMD). Although vascular endothelial growth factor (VEGF) blockade for NV-AMD has shown beneficial outcomes, unmet medical needs for patients refractory or tachyphylactic to anti-VEGF therapy exist. In addition, the treatment could exacerbate choriocapillary rarefaction, necessitating advanced treatment for fundamental recovery from NV-AMD. In this study, Tie2 activation by angiopoietin-2-binding and Tie2-activating antibody (ABTAA) presents a therapeutic strategy for NV-AMD. Conditional Tie2 deletion impeded choriocapillary maintenance, rendering eyes susceptible to NV-AMD development. Moreover, in a NV-AMD mouse model, ABTAA not only suppressed choroidal neovascularization (CNV) and vascular leakage but also regenerated the choriocapillaris and relieved hypoxia. Conversely, VEGF blockade degenerated the choriocapillaris and exacerbated hypoxia, although it suppressed CNV and vascular leakage. Together, we establish that angiopoietin-Tie2 signaling is critical for choriocapillary maintenance and that ABTAA represents an alternative, combinative therapeutic strategy for NV-AMD by alleviating anti-VEGF adverse effects.
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