Mammano, Fabio (2022) Data related to eBiomedicine 2023 Article Number 104453 titled "Antibody gene transfer treatment drastically improves epidermal pathology in a keratitis ichthyosis deafness syndrome model using male mice". [Data Collection]
This is the latest version of this item.
Available Versions of this Item
- Data related to eBiomedicine 2023 Article Number 104453 titled "Antibody gene transfer treatment drastically improves epidermal pathology in a keratitis ichthyosis deafness syndrome model using male mice". (deposited 24 Jan 2023 09:13) [Currently Displayed]
Collection description
SUMMARY 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. The recent development of specific monoclonal antibodies (mAbs) that block the acquired HC activity, and the availability of mouse models that replicate the skin pathology of KID syndrome, allow this deficiency to be directly addressed. In this study, we aimed to assess inhibition of mutant Cx HC activity with anti-HC monoclonal antibodies as therapeutic target in KID syndrome. Methods We used Adeno Associated Virus (AAV) mediated mAb gene transfer (AAVmAb) to treat the epidermal features of KID syndrome in a mouse model of the human disease with a well-characterized HC blocking antibody. Findings We demonstrate that in vivo AAVmAb treatment, via caudal vein injection of the mAb-encoding AAV vector, 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 Fondazione Telethon grant GGP19148 to FM; University of Padova grant Prot. BIRD187130 to FM; Foundation for Ichthyosis and Related Skin Types (FIRST) to TWW; National Institutes of Health grant EY 026911 to TWW.
| DOI: |  10.25430/researchdata.cab.unipd.it.00000802 |
||||||
|---|---|---|---|---|---|---|---|
| Keywords: | Genodermatosis, connexin 26, adeno-associated viral vectors, in vivo preclinical study. | ||||||
| Subjects: | Life Sciences > Cellular and Developmental Biology: Cell biology, cell physiology, signal transduction, organogenesis, developmental genetics, pattern formation, stem cell biology, in plants and animals and where appropriate in microorganisms > Cell junctions, cell-adhesion, cell communication and the extracellular matrix Life Sciences > Cellular and Developmental Biology: Cell biology, cell physiology, signal transduction, organogenesis, developmental genetics, pattern formation, stem cell biology, in plants and animals and where appropriate in microorganisms > Cell cycle, division and growth Life Sciences > Applied Medical Technologies, Diagnostics, Therapies, and Public Health: Development of treatment of diseases, pharmacology, clinical medicine, regenerative medicine, epidemiology and public for diagnosis, monitoring and tools health > Pharmacology and pharmacogenomics (including drug discovery and design, drug delivery and therapy, toxicology) Life Sciences > Applied Medical Technologies, Diagnostics, Therapies, and Public Health: Development of treatment of diseases, pharmacology, clinical medicine, regenerative medicine, epidemiology and public for diagnosis, monitoring and tools health > Applied gene and cell therapies, regenerative medicine |
||||||
| Department: | Departments > Dipartimento di Fisica e Astronomia "Galileo Galilei" (DFA) | ||||||
| Depositing User: | Fabio Mammano | ||||||
| Date Deposited: | 24 Jan 2023 09:13 | ||||||
| Last Modified: | 24 Jan 2023 09:17 | ||||||
| Creators/Authors: |
|
||||||
| Type of data: | Text | ||||||
| Contributors: |
|
||||||
| Collection period: |
|
||||||
| Geographic coverage: | Italy, Lazio Region, CNR Monterotondo, via E. Ramarini No. 32, 00015 Monterotondo | ||||||
| Data collection method: | Quantification of circulating mAb levels by ELISA. In vivo quantification of lesional skin area based on ratiometric reflectance imaging. In vivo DAPI uptake assay. Histology and immunofluorescence. | ||||||
| Statement on legal, ethical and access issues: | All animal procedures were agreed upon, reviewed and approved by local animal welfare oversight bodies and were performed with the approval and direct supervision of the CNR-IBBC/Infrafrontier – Animal Welfare and Ethical Review Body (AWERB), in accordance with general guidelines regarding animal experimentation, approved by the Italian Ministry of Health, in compliance with the Legislative Decree 26/2014 (ref. Project license 603/2018-PR and 632/2019-PR), transposing the 2010/63/EU Directive on protection of animals used in research) and in adherence to the NIH Guide for the Care and Use of Laboratory Animals and recommendations from both ARRIVE and PREPARE guidelines. | ||||||
| Data processing and preparation activities: | For image processing we used the open-source software ImageJ/Fiji (ImageJ-win64) and related plugins. For data analysis and plotting we used Matlab (R2019a, The MathWorks, Inc., Natick, MA, USA). Statistics Sample sizes (n) for each analysis are stated in the figure legends. The null-hypothesis of normally distributed samples was verified using the Shapiro-Wilk test. For multiple comparison, parametric analysis of variance was performed by one-way ANOVA; for pairwise comparisons, the two-tailed t-test was used. In the case of multiple comparison testing, a Bonferroni correction was applied after the ANOVA test. Non-parametric statistical analysis of variance for pairwise comparison was performed using the Mann-Whitney U test. In all statistical analysis, a p-value (P) < 0.05 indicates statistical significance. | ||||||
| Resource language: | English | ||||||
| Metadata language: | English | ||||||
| Publisher: | Research Data Unipd | ||||||
| Related publications: | |||||||
| Date: | 29 December 2022 | ||||||
| Copyright holders: | The Author | ||||||
| URI: | https://researchdata.cab.unipd.it/id/eprint/817 |
orcid.org/0000-0003-3751-1691
