<br>具有 COL17A1 无义突变的交界性大疱性表皮松解症通读疗法的优化策略,Journal of Investigative Dermatology

当前位置： X-MOL 学术 › J. Invest. Dermatol. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

具有 COL17A1 无义突变的交界性大疱性表皮松解症通读疗法的优化策略
Journal of Investigative Dermatology ( IF 5.7 ) Pub Date : 2024-03-22 , DOI: 10.1016/j.jid.2024.02.027
Saliha Beyza Sayar ₁ , Cristina Has ₁

Affiliation

通读疗法抑制过早终止密码子并诱导通读活性，从而恢复缺失的蛋白质。氨基糖苷类作为通读药物在不同的人类遗传性疾病（包括遗传性皮肤病）中被广泛研究。我们之前的工作表明，氨基糖苷类药物会影响无义突变，是减轻疾病严重程度的一种治疗选择。然而，C17 缺陷的交界性大疱性表皮松解症角质形成细胞中恢复的 XVII 型胶原 (C17) 量相对于正常角质形成细胞为 <1%，并且只有在高剂量庆大霉素处理后才能实现，从而诱导深层转录变化。因此，在这项研究中，我们设计了一种将氨基糖苷类药物与已知可减少其副作用的化合物相结合的策略。我们开发了翻译通读诱导药物混合物，版本 5 含有低剂量的氨基糖苷类、CC-90009、NMDI-14、褪黑激素和夹竹桃素，能够诱导约 20% 的缺失 C17，而不会产生细胞毒性或对细胞产生影响。体外伤口闭合。转化通读诱导药物混合物，版本 5 显着诱导表达并恢复 C17 缺陷的交界性大疱性表皮松解症角质形成细胞的促炎表型。对这种药物混合物的稳定性、渗透性和局部治疗功效的评价仍有待确定。转化通读诱导药物鸡尾酒版本 5 可能代表了一种改进的治疗策略，用于治疗大疱性交界性表皮松解症和其他遗传性皮肤病。

"点击查看英文标题和摘要"

Strategy for the Optimization of Read-Through Therapy for Junctional Epidermolysis Bullosa with COL17A1 Nonsense Mutation

Read-through therapy suppresses premature termination codons and induces read-through activity, consequently restoring missing proteins. Aminoglycosides are widely studied as read-through drugs in different human genetic disorders, including hereditary skin diseases. Our previous work revealed that aminoglycosides affect nonsense mutations and represent a therapeutic option to alleviate disease severity. However, the amount of restored type XVII collagen (C17) in C17-deficient junctional epidermolysis bullosa keratinocytes was <1% relative to that in normal keratinocytes and was achieved only after high-dose gentamicin treatment, which induced deep transcriptional changes. Therefore, in this study, we designed a strategy combining aminoglycosides with compounds known to reduce their side effects. We developed translational read-through–inducing drug cocktail, version 5 containing low dosage of aminoglycosides, CC-90009, NMDI-14, melatonin, and apocynin that was able to induce about 20% of missing C17 without cell toxicity or an effect on in vitro wound closure. Translational read-through–inducing drugs cocktail, version 5 significantly induced expression and reverted the proinflammatory phenotype of C17-deficient junctional epidermolysis bullosa keratinocytes. Evaluation of this drug cocktail regarding its stability, penetration, and efficacy as a topical treatment remains to be determined. Translational read-through–inducing drug cocktail, version 5 might represent an improved therapeutic strategy for junctional epidermolysis bullosa and for other genetic skin disorders.

更新日期：2024-03-22

点击分享查看原文

点击收藏

公开下载

阅读更多本刊新发论文本刊介绍/投稿指南