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

Yuanyuan Kuang, Veronica Zorzi, Damiano Buratto, Gaia Ziraldo, Flavia Mazzarda, Chiara Peres, Chiara Nardin, Anna Maria Salvatore, Francesco Chiani, Ferdinando Scavizzi, Marcello Raspa, Min Qiang, Youjun Chu, Xiaojie Shi, Yu Li, Lili Liu, Yaru Shi, Francesco Zonta, Guang Yang*, Richard A. LernerFabio Mammano

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

23 Citations (Scopus)

Abstract

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 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. 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 Ca2+ 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 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.

Original languageEnglish
Article number102825
JournalEBioMedicine
Volume57
DOIs
Publication statusPublished - Jul 2020
Externally publishedYes

Keywords

  • ATP
  • Antibody drug discovery
  • Calcium
  • Epidermis
  • Genodermatosis
  • Sebocytes

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