Antibody gene transfer treatment drastically improves epidermal pathology in a keratitis ichthyosis deafness syndrome model using male mice.
Antibody gene transfer treatment drastically improves epidermal pathology in a keratitis ichthyosis deafness syndrome model using male mice.
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DOI：
10.1016/j.ebiom.2023.104453
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发表时间：
2023-03
期刊：
影响因子：
11.1
通讯作者：
Mammano, Fabio
中科院分区：
文献类型：
--
作者：
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
角膜炎鱼鳞病耳聋 (KID) 综合征是一种罕见疾病，由编码连接蛋白 (Cx) 26 的 GJB2 基因中的半通道 (HC) 激活功能获得性突变引起，目前尚无治愈方法，也没有基于致病机制的治疗方法。我们应用腺相关病毒 (AAV) 介导的单克隆抗体基因转移 (AAVmAb) 来治疗 KID 综合征的表皮特征，并使用复制人类疾病皮肤病理学的小鼠模型的雄性小鼠，通过充分表征的 HC 阻断抗体。我们证明，体内 AAVmAb 治疗除了阻断体内表皮中突变 HC 的活性外，还显着减少了 KID 病变的大小和厚度。我们还表明，AAVmAb 治疗消除了异常的角质形成细胞增殖和增大的细胞大小，减少了细胞凋亡，并恢复了角蛋白表达的正常分布。我们的研究结果强化了 HC 活性增加在与 KID 综合征相关的皮肤病理学中所发挥的关键作用。他们还强调了抗 HC 单克隆抗体与基于基因的递送系统相结合用于治疗这种疾病的潜在机制的临床潜力。抑制 HC 活性是 KID 综合征的理想治疗靶点，针对突变 HC 的单克隆抗体的基因递送可以构成治疗这种不治之症的新治疗干预措施的基础。 授予 GGP19148 并授予 Prot。 BIRD187130 转 FM； （首先）并向 TWW 授予 EY 026911。
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. grant GGP19148 and grant Prot. BIRD187130 to FM; (FIRST) and grant EY 026911 to TWW.
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影响因子：
17.1
作者：
Cantore, Alessio;Ranzani, Marco;Naldini, Luigi
通讯作者：
Naldini, Luigi
DOI：
10.1073/pnas.95.26.15735
发表时间：
1998-12-22
影响因子：
11.1
作者：
Cotrina, ML;Lin, JHC;Nedergaard, M
通讯作者：
Nedergaard, M
DOI：
10.3390/pathogens11070756
发表时间：
2022-07-03
期刊：
Pathogens (Basel, Switzerland)
影响因子：
--
作者：
通讯作者：
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影响因子：
--
作者：
Cardiff, Robert D;Miller, Claramae H;Munn, Robert J
通讯作者：
Munn, Robert J
影响因子：
3.5
作者：
Bosen, Felicitas;Schuetz, Melanie;Willecke, Klaus
通讯作者：
Willecke, Klaus