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A potent antagonist antibody targeting connexin hemichannels alleviates Clouston syndrome symptoms in mutant mice.

Authors
  • Kuang, Yuanyuan1
  • Zorzi, Veronica2
  • Buratto, Damiano3
  • Ziraldo, Gaia2
  • Mazzarda, Flavia4
  • Peres, Chiara5
  • Nardin, Chiara5
  • Salvatore, Anna Maria6
  • Chiani, Francesco6
  • Scavizzi, Ferdinando6
  • Raspa, Marcello6
  • Qiang, Min3
  • Chu, Youjun3
  • Shi, Xiaojie3
  • Li, Yu1
  • Liu, Lili3
  • Shi, Yaru3
  • Zonta, Francesco3
  • Yang, Guang7
  • Lerner, Richard A8
  • And 1 more
  • 1 Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China; School of Life Science and Technology, ShanghaiTech University, 201210 Shanghai, China; Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 200031 Shanghai, China; University of Chinese Academy of Sciences, 100049 Beijing, China. , (China)
  • 2 CNR Institute of Biochemistry and Cell Biology, 00015 Monterotondo, Italy; Institute of Otorhinolaryngology, Università Cattolica del Sacro Cuore, 00168 Rome, Italy. , (Italy)
  • 3 Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China. , (China)
  • 4 CNR Institute of Biochemistry and Cell Biology, 00015 Monterotondo, Italy; Department of Science, Roma3 University, 00146 Rome, Italy. , (Italy)
  • 5 CNR Institute of Biochemistry and Cell Biology, 00015 Monterotondo, Italy; Department of Physics and Astronomy "G. Galilei", University of Padova, 35131 Padova, Italy. , (Italy)
  • 6 CNR Institute of Biochemistry and Cell Biology, 00015 Monterotondo, Italy. , (Italy)
  • 7 Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China. Electronic address: [email protected] , (China)
  • 8 Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China; Department of Chemistry, Scripps Research Institute, La Jolla, CA 92037, U.S.A.. Electronic address: [email protected] , (China)
  • 9 Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China; CNR Institute of Biochemistry and Cell Biology, 00015 Monterotondo, Italy; Department of Physics and Astronomy "G. Galilei", University of Padova, 35131 Padova, Italy. Electronic address: [email protected] , (China)
Type
Published Article
Journal
EBioMedicine
Publisher
Elsevier
Publication Date
Jul 01, 2020
Volume
57
Pages
102825–102825
Identifiers
DOI: 10.1016/j.ebiom.2020.102825
PMID: 32553574
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Numerous currently incurable human diseases have been causally linked to mutations in connexin (Cx) genes. In several instances, pathological mutations generate abnormally active Cx hemichannels, referred to also as "leaky" hemichannels. The goal of this study was to assay the in vivo efficacy of a potent antagonist antibody targeting Cx hemichannels. We employed the antibody to treat Cx30A88V/A88V adult mutant mice, the only available animal model of Clouston syndrome, a rare orphan disease caused by Cx30 p.A88V leaky hemichannels. To gain mechanistic insight into antibody action, we also performed patch clamp recordings, Ca2+ imaging and ATP release assay in vitro. Two weeks of antibody treatment sufficed to repress cell hyperproliferation in skin and reduce hypertrophic sebaceous glands (SGs) to wild type (wt) levels. These effects were obtained whether mutant mice were treated topically, by application of an antibody cream formulation, or systemically, by intraperitoneal antibody injection. Experiments with mouse primary keratinocytes and HaCaT cells revealed the antibody blocked Ca2+ influx and diminished ATP release through leaky Cx30 p.A88V hemichannels. Our results show anti-Cx antibody treatment was effective in vivo and sufficient to counteract the effects of pathological connexin expression in Cx30A88V/A88V mice. In vitro experiments suggest antibodies gained control over leaky hemichannels and contributed to restoring epidermal homeostasis. Therefore, regulating cell physiology by antibodies targeting the extracellular domain of Cxs may enforce an entirely new therapeutic strategy. These findings support the further development of antibodies as drugs to address unmet medical needs for Cx-related diseases. FUND: Fondazione Telethon, GGP19148; University of Padova, SID/BIRD187130; Consiglio Nazionale delle Ricerche, DSB.AD008.370.003\TERABIO-IBCN; National Science Foundation of China, 31770776; Science and Technology Commission of Shanghai Municipality, 16DZ1910200. Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.

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