背景:角膜炎性鱼鳞病性耳聋(KID)综合征是由编码连接蛋白(Cx)26的GJB2基因中的半通道(HC)激活功能获得突变引起的罕见疾病,或基于疾病病因机制的当前治疗方法。
方法:我们应用腺相关病毒(AAV)介导的mAb基因转移(AAVmAb),使用具有充分表征的HC阻断抗体,使用复制人类疾病的皮肤病理学的鼠模型的雄性小鼠,治疗KID综合征的表皮特征。
结果:我们证明体内AAVmAb治疗显着减少了KID病变的大小和厚度,除了阻断体内表皮中突变HCs的活性。我们还显示,AAVmAb治疗消除了异常的角质形成细胞增殖和细胞大小增大,细胞凋亡减少,并恢复了角蛋白表达的正态分布。
结论:我们的发现加强了HC活性增加在与KID综合征相关的皮肤病理学中所起的关键作用。他们还强调了抗HCmAb与基于遗传的递送系统结合用于治疗这种疾病的潜在机制基础的临床潜力。抑制HC活性是治疗KID综合征的理想靶点,而靶向突变HCs的单克隆抗体的基因传递可能成为治疗这种不治之症的新的治疗干预措施的基础.
背景:FondazioneTelethon授予GGP19148和帕多瓦大学授予Prot。BIRD187130至FM;鱼鳞病及相关皮肤类型基金会(FIRST)和美国国立卫生研究院将EY026911授予TWW。
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.
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.
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.
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.