Antibody gene transfer treatment drastically improves epidermal pathology in a keratitis ichthyosis deafness syndrome model using male mice.
Adeno-associated viral vectors
Connexin 26
Genodermatosis
In vivo preclinical study
Journal
EBioMedicine
ISSN: 2352-3964
Titre abrégé: EBioMedicine
Pays: Netherlands
ID NLM: 101647039
Informations de publication
Date de publication:
Mar 2023
Mar 2023
Historique:
received:
23
09
2022
revised:
30
12
2022
accepted:
11
01
2023
pubmed:
4
2
2023
medline:
15
3
2023
entrez:
3
2
2023
Statut:
ppublish
Résumé
Keratitis ichthyosis deafness (KID) syndrome is a rare disorder caused by hemichannel (HC) activating gain-of-function mutations in the GJB2 gene encoding connexin (Cx) 26, for which there is no cure, or current treatments based upon the mechanism of disease causation. We applied Adeno Associated Virus (AAV) mediated mAb gene transfer (AAVmAb) to treat the epidermal features of KID syndrome with a well-characterized HC blocking antibody using male mice of a murine model that replicates the skin pathology of the human disease. We demonstrate that in vivo AAVmAb treatment significantly reduced the size and thickness of KID lesions, in addition to blocking activity of mutant HCs in the epidermis in vivo. We also show that AAVmAb treatment eliminated abnormal keratinocyte proliferation and enlarged cell size, decreased apoptosis, and restored the normal distribution of keratin expression. Our findings reinforce the critical role played by increased HC activity in the skin pathology associated with KID syndrome. They also underscore the clinical potential of anti-HC mAbs coupled with genetic based delivery systems for treating the underlying mechanistic basis of this disorder. Inhibition of HC activity is an ideal therapeutic target in KID syndrome, and the genetic delivery of mAbs targeted against mutant HCs could form the basis of new therapeutic interventions to treat this incurable disease. Fondazione Telethon grant GGP19148 and University of Padova grant Prot. BIRD187130 to FM; Foundation for Ichthyosis and Related Skin Types (FIRST) and National Institutes of Health grant EY 026911 to TWW.
Sections du résumé
BACKGROUND
BACKGROUND
Keratitis ichthyosis deafness (KID) syndrome is a rare disorder caused by hemichannel (HC) activating gain-of-function mutations in the GJB2 gene encoding connexin (Cx) 26, for which there is no cure, or current treatments based upon the mechanism of disease causation.
METHODS
METHODS
We applied Adeno Associated Virus (AAV) mediated mAb gene transfer (AAVmAb) to treat the epidermal features of KID syndrome with a well-characterized HC blocking antibody using male mice of a murine model that replicates the skin pathology of the human disease.
FINDINGS
RESULTS
We demonstrate that in vivo AAVmAb treatment significantly reduced the size and thickness of KID lesions, in addition to blocking activity of mutant HCs in the epidermis in vivo. We also show that AAVmAb treatment eliminated abnormal keratinocyte proliferation and enlarged cell size, decreased apoptosis, and restored the normal distribution of keratin expression.
INTERPRETATION
CONCLUSIONS
Our findings reinforce the critical role played by increased HC activity in the skin pathology associated with KID syndrome. They also underscore the clinical potential of anti-HC mAbs coupled with genetic based delivery systems for treating the underlying mechanistic basis of this disorder. Inhibition of HC activity is an ideal therapeutic target in KID syndrome, and the genetic delivery of mAbs targeted against mutant HCs could form the basis of new therapeutic interventions to treat this incurable disease.
FUNDING
BACKGROUND
Fondazione Telethon grant GGP19148 and University of Padova grant Prot. BIRD187130 to FM; Foundation for Ichthyosis and Related Skin Types (FIRST) and National Institutes of Health grant EY 026911 to TWW.
Identifiants
pubmed: 36736132
pii: S2352-3964(23)00018-X
doi: 10.1016/j.ebiom.2023.104453
pmc: PMC9926223
pii:
doi:
Substances chimiques
Antibodies
0
Connexins
0
Gjb2 protein, mouse
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
104453Subventions
Organisme : NEI NIH HHS
ID : R01 EY026911
Pays : United States
Informations de copyright
Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests Drs. G. Yang, F. Zonta and F. Mammano report a patent family: “WO2017128880 – Fully human antibody specifically inhibiting connexin 26”, Inventors: Qu Z, Yang G, Mammano F, Zonta F, International application number: PCT/CN2016/109847, granted to ShanghaiTech University; and a patent family “WO2020237491 – Composition and Methods to treat Ectodermal Dysplasia 2, Clouston Type”, Inventors: Mammano F, Yang G, Zonta F, International Application No.: PCT/CN2019/088689, pending to ShanghaiTech University. M. Rigamonti is an employee of Tecniplast SpA. Tecniplast SpA did not have any role in the study design, decision to publish, or preparation of the manuscript. All other authors declare that they have no competing interests.