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A potent antagonist antibody targeting connexin hemichannels alleviates Clouston syndrome symptoms in mutant mice
BACKGROUND: 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 ef...
Autores principales: | , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7378960/ https://www.ncbi.nlm.nih.gov/pubmed/32553574 http://dx.doi.org/10.1016/j.ebiom.2020.102825 |
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author | Kuang, Yuanyuan Zorzi, Veronica Buratto, Damiano Ziraldo, Gaia Mazzarda, Flavia Peres, Chiara Nardin, Chiara Salvatore, Anna Maria Chiani, Francesco Scavizzi, Ferdinando Raspa, Marcello Qiang, Min Chu, Youjun Shi, Xiaojie Li, Yu Liu, Lili Shi, Yaru Zonta, Francesco Yang, Guang Lerner, Richard A. Mammano, Fabio |
author_facet | Kuang, Yuanyuan Zorzi, Veronica Buratto, Damiano Ziraldo, Gaia Mazzarda, Flavia Peres, Chiara Nardin, Chiara Salvatore, Anna Maria Chiani, Francesco Scavizzi, Ferdinando Raspa, Marcello Qiang, Min Chu, Youjun Shi, Xiaojie Li, Yu Liu, Lili Shi, Yaru Zonta, Francesco Yang, Guang Lerner, Richard A. Mammano, Fabio |
author_sort | Kuang, Yuanyuan |
collection | PubMed |
description | BACKGROUND: 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. METHODS: We employed the antibody to treat Cx30(A88V/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, Ca(2+) imaging and ATP release assay in vitro. FINDINGS: 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 Ca(2+) influx and diminished ATP release through leaky Cx30 p.A88V hemichannels. INTERPRETATION: Our results show anti-Cx antibody treatment was effective in vivo and sufficient to counteract the effects of pathological connexin expression in Cx30(A88V/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. |
format | Online Article Text |
id | pubmed-7378960 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-73789602020-07-24 A potent antagonist antibody targeting connexin hemichannels alleviates Clouston syndrome symptoms in mutant mice Kuang, Yuanyuan Zorzi, Veronica Buratto, Damiano Ziraldo, Gaia Mazzarda, Flavia Peres, Chiara Nardin, Chiara Salvatore, Anna Maria Chiani, Francesco Scavizzi, Ferdinando Raspa, Marcello Qiang, Min Chu, Youjun Shi, Xiaojie Li, Yu Liu, Lili Shi, Yaru Zonta, Francesco Yang, Guang Lerner, Richard A. Mammano, Fabio EBioMedicine Research paper BACKGROUND: 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. METHODS: We employed the antibody to treat Cx30(A88V/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, Ca(2+) imaging and ATP release assay in vitro. FINDINGS: 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 Ca(2+) influx and diminished ATP release through leaky Cx30 p.A88V hemichannels. INTERPRETATION: Our results show anti-Cx antibody treatment was effective in vivo and sufficient to counteract the effects of pathological connexin expression in Cx30(A88V/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. Elsevier 2020-06-15 /pmc/articles/PMC7378960/ /pubmed/32553574 http://dx.doi.org/10.1016/j.ebiom.2020.102825 Text en © 2020 The Author(s) http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Research paper Kuang, Yuanyuan Zorzi, Veronica Buratto, Damiano Ziraldo, Gaia Mazzarda, Flavia Peres, Chiara Nardin, Chiara Salvatore, Anna Maria Chiani, Francesco Scavizzi, Ferdinando Raspa, Marcello Qiang, Min Chu, Youjun Shi, Xiaojie Li, Yu Liu, Lili Shi, Yaru Zonta, Francesco Yang, Guang Lerner, Richard A. Mammano, Fabio A potent antagonist antibody targeting connexin hemichannels alleviates Clouston syndrome symptoms in mutant mice |
title | A potent antagonist antibody targeting connexin hemichannels alleviates Clouston syndrome symptoms in mutant mice |
title_full | A potent antagonist antibody targeting connexin hemichannels alleviates Clouston syndrome symptoms in mutant mice |
title_fullStr | A potent antagonist antibody targeting connexin hemichannels alleviates Clouston syndrome symptoms in mutant mice |
title_full_unstemmed | A potent antagonist antibody targeting connexin hemichannels alleviates Clouston syndrome symptoms in mutant mice |
title_short | A potent antagonist antibody targeting connexin hemichannels alleviates Clouston syndrome symptoms in mutant mice |
title_sort | potent antagonist antibody targeting connexin hemichannels alleviates clouston syndrome symptoms in mutant mice |
topic | Research paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7378960/ https://www.ncbi.nlm.nih.gov/pubmed/32553574 http://dx.doi.org/10.1016/j.ebiom.2020.102825 |
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