近日，德国自由大学教授Sarah Hedtrich及其小组开发出基于脂质纳米颗粒的人类皮肤模型先天性鱼鳞病引起突变的非病毒原位基因编辑。这一研究成果发表在2026年1月27日出版的国际学术期刊《细胞—干细胞》上。

小组报道了人类疾病模型中最常见的ARCI-导管突变TGM1 c.877-2A>G（一种剪接位点畸变）的临床相关原位校正。靶向皮肤屏障调节，然后局部应用包装成脂质纳米颗粒的胞嘧啶碱基编辑器eTd，可使皮肤组织中野生型转谷氨酰胺酶1活性恢复约30%的功能。毒性研究和全面的脱靶分析表明，即使在重复使用后，通过高灵敏度的方法（包括解吸电喷雾电离（DESI）代谢成像）确定，在没有脂质纳米颗粒的全身分布或遗传货物的情况下，也具有良好的安全性。本研究提供了关于基因皮肤病导管突变原位基因校正可行性的全面临床前数据，展示了其治疗潜力，并为治疗严重遗传性皮肤病的下一代治疗方法铺平了道路。

研究人员表示，常染色体隐性先天性鱼鳞病（ARCI）是指一组罕见的，高度衰弱的皮肤疾病，严重损害患者的生活质量，缺乏任何有效的治疗选择。

附：英文原文

Title: Lipid nanoparticle-based non-viral in situ gene editing of congenital ichthyosis-causing mutations in human skin models

Author: Dilem Ceren Apaydin, Gaurav Sadhnani, Tiffany Carlaw, Jan Renziehausen, Elena Lizunova, Viviane Filor, Anna Hiller, Sophia Brumhard, Vincent Halim, Ulrike Brüning, Johannes Bischof, Rafaela Horbach Marodin, Daniel Z. Kurek, Manuel Rhiel, Sandra Ammann, Tatjana I. Cornu, Toni Cathomen, Leif Erik Sander, Benedikt Obermayer, Fabian Coscia, Jennifer Kirwan, Ulrich Koller, Achim D. Gruber, Wolfgang Bumer, Sarah Hedtrich

Issue&Volume: 2026-01-27

Abstract: Autosomal recessive congenital ichthyosis (ARCI) refers to a group of rare, highly debilitating skin disorders that significantly impair patients’ quality of life and lack any effective treatment options. Here, we report clinically relevant in situ correction of the most common ARCI-causing mutation, TGM1 c.877-2A>G, a splice-site aberration, in human disease models. Targeted skin barrier modulation followed by topical application of the cytosine base editor eTd packaged into lipid nanoparticles yielded functional restoration of ～30% of wild-type transglutaminase 1 activity in skin tissue. Toxicity studies and comprehensive off-target analysis demonstrated an excellent safety profile even after repeated application, without systemic distribution of the lipid nanoparticles or the genetic cargo as determined via highly sensitive methods, including desorption electrospray ionization (DESI) metabolic imaging. This study presents comprehensive preclinical data on the feasibility of in situ gene correction of genodermatoses-causing mutations, showcasing its therapeutic potential and paving the way for curative next-generation treatments for severe genetic skin diseases.

DOI: 10.1016/j.stem.2026.01.001

Source: https://www.cell.com/cell-stem-cell/abstract/S1934-5909(26)00024-X