Cargando…

Antibody gene transfer treatment drastically improves epidermal pathology in a keratitis ichthyosis deafness syndrome model using male mice

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: We applie...

Descripción completa

Detalles Bibliográficos
Autores principales: Peres, Chiara, Sellitto, Caterina, Nardin, Chiara, Putti, Sabrina, Orsini, Tiziana, Di Pietro, Chiara, Marazziti, Daniela, Vitiello, Adriana, Calistri, Arianna, Rigamonti, Mara, Scavizzi, Ferdinando, Raspa, Marcello, Zonta, Francesco, Yang, Guang, White, Thomas W., Mammano, Fabio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9926223/
https://www.ncbi.nlm.nih.gov/pubmed/36736132
http://dx.doi.org/10.1016/j.ebiom.2023.104453
_version_ 1784888232673017856
author Peres, Chiara
Sellitto, Caterina
Nardin, Chiara
Putti, Sabrina
Orsini, Tiziana
Di Pietro, Chiara
Marazziti, Daniela
Vitiello, Adriana
Calistri, Arianna
Rigamonti, Mara
Scavizzi, Ferdinando
Raspa, Marcello
Zonta, Francesco
Yang, Guang
White, Thomas W.
Mammano, Fabio
author_facet Peres, Chiara
Sellitto, Caterina
Nardin, Chiara
Putti, Sabrina
Orsini, Tiziana
Di Pietro, Chiara
Marazziti, Daniela
Vitiello, Adriana
Calistri, Arianna
Rigamonti, Mara
Scavizzi, Ferdinando
Raspa, Marcello
Zonta, Francesco
Yang, Guang
White, Thomas W.
Mammano, Fabio
author_sort Peres, Chiara
collection PubMed
description 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: 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: 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: 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: 10.13039/501100002426Fondazione Telethon grant GGP19148 and 10.13039/501100003500University of Padova grant Prot. BIRD187130 to FM; 10.13039/100002886Foundation for Ichthyosis and Related Skin Types (FIRST) and 10.13039/100000002National Institutes of Health grant EY 026911 to TWW.
format Online
Article
Text
id pubmed-9926223
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher Elsevier
record_format MEDLINE/PubMed
spelling pubmed-99262232023-02-15 Antibody gene transfer treatment drastically improves epidermal pathology in a keratitis ichthyosis deafness syndrome model using male mice Peres, Chiara Sellitto, Caterina Nardin, Chiara Putti, Sabrina Orsini, Tiziana Di Pietro, Chiara Marazziti, Daniela Vitiello, Adriana Calistri, Arianna Rigamonti, Mara Scavizzi, Ferdinando Raspa, Marcello Zonta, Francesco Yang, Guang White, Thomas W. Mammano, Fabio eBioMedicine Articles 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: 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: 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: 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: 10.13039/501100002426Fondazione Telethon grant GGP19148 and 10.13039/501100003500University of Padova grant Prot. BIRD187130 to FM; 10.13039/100002886Foundation for Ichthyosis and Related Skin Types (FIRST) and 10.13039/100000002National Institutes of Health grant EY 026911 to TWW. Elsevier 2023-02-01 /pmc/articles/PMC9926223/ /pubmed/36736132 http://dx.doi.org/10.1016/j.ebiom.2023.104453 Text en © 2023 The Authors https://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 Articles
Peres, Chiara
Sellitto, Caterina
Nardin, Chiara
Putti, Sabrina
Orsini, Tiziana
Di Pietro, Chiara
Marazziti, Daniela
Vitiello, Adriana
Calistri, Arianna
Rigamonti, Mara
Scavizzi, Ferdinando
Raspa, Marcello
Zonta, Francesco
Yang, Guang
White, Thomas W.
Mammano, Fabio
Antibody gene transfer treatment drastically improves epidermal pathology in a keratitis ichthyosis deafness syndrome model using male mice
title Antibody gene transfer treatment drastically improves epidermal pathology in a keratitis ichthyosis deafness syndrome model using male mice
title_full Antibody gene transfer treatment drastically improves epidermal pathology in a keratitis ichthyosis deafness syndrome model using male mice
title_fullStr Antibody gene transfer treatment drastically improves epidermal pathology in a keratitis ichthyosis deafness syndrome model using male mice
title_full_unstemmed Antibody gene transfer treatment drastically improves epidermal pathology in a keratitis ichthyosis deafness syndrome model using male mice
title_short Antibody gene transfer treatment drastically improves epidermal pathology in a keratitis ichthyosis deafness syndrome model using male mice
title_sort antibody gene transfer treatment drastically improves epidermal pathology in a keratitis ichthyosis deafness syndrome model using male mice
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9926223/
https://www.ncbi.nlm.nih.gov/pubmed/36736132
http://dx.doi.org/10.1016/j.ebiom.2023.104453
work_keys_str_mv AT pereschiara antibodygenetransfertreatmentdrasticallyimprovesepidermalpathologyinakeratitisichthyosisdeafnesssyndromemodelusingmalemice
AT sellittocaterina antibodygenetransfertreatmentdrasticallyimprovesepidermalpathologyinakeratitisichthyosisdeafnesssyndromemodelusingmalemice
AT nardinchiara antibodygenetransfertreatmentdrasticallyimprovesepidermalpathologyinakeratitisichthyosisdeafnesssyndromemodelusingmalemice
AT puttisabrina antibodygenetransfertreatmentdrasticallyimprovesepidermalpathologyinakeratitisichthyosisdeafnesssyndromemodelusingmalemice
AT orsinitiziana antibodygenetransfertreatmentdrasticallyimprovesepidermalpathologyinakeratitisichthyosisdeafnesssyndromemodelusingmalemice
AT dipietrochiara antibodygenetransfertreatmentdrasticallyimprovesepidermalpathologyinakeratitisichthyosisdeafnesssyndromemodelusingmalemice
AT marazzitidaniela antibodygenetransfertreatmentdrasticallyimprovesepidermalpathologyinakeratitisichthyosisdeafnesssyndromemodelusingmalemice
AT vitielloadriana antibodygenetransfertreatmentdrasticallyimprovesepidermalpathologyinakeratitisichthyosisdeafnesssyndromemodelusingmalemice
AT calistriarianna antibodygenetransfertreatmentdrasticallyimprovesepidermalpathologyinakeratitisichthyosisdeafnesssyndromemodelusingmalemice
AT rigamontimara antibodygenetransfertreatmentdrasticallyimprovesepidermalpathologyinakeratitisichthyosisdeafnesssyndromemodelusingmalemice
AT scavizziferdinando antibodygenetransfertreatmentdrasticallyimprovesepidermalpathologyinakeratitisichthyosisdeafnesssyndromemodelusingmalemice
AT raspamarcello antibodygenetransfertreatmentdrasticallyimprovesepidermalpathologyinakeratitisichthyosisdeafnesssyndromemodelusingmalemice
AT zontafrancesco antibodygenetransfertreatmentdrasticallyimprovesepidermalpathologyinakeratitisichthyosisdeafnesssyndromemodelusingmalemice
AT yangguang antibodygenetransfertreatmentdrasticallyimprovesepidermalpathologyinakeratitisichthyosisdeafnesssyndromemodelusingmalemice
AT whitethomasw antibodygenetransfertreatmentdrasticallyimprovesepidermalpathologyinakeratitisichthyosisdeafnesssyndromemodelusingmalemice
AT mammanofabio antibodygenetransfertreatmentdrasticallyimprovesepidermalpathologyinakeratitisichthyosisdeafnesssyndromemodelusingmalemice