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"

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.