德克萨斯大学Daniel J. Siegwart研究组取得一项新突破。他们报道了用于多器官碱基编辑的双排序LNPs。这一研究成果发表在2025年6月2日出版的国际学术期刊《自然—生物技术》上。

该课题组研究人员开发了双选择性器官靶向脂质纳米颗粒（SORT LNPs），将碱基编辑器输送到肝脏和肺部。双SORT LNPs纠正了PiZ突变，在肝细胞中实现了40%的纠正编辑，在肺AT2细胞中实现了10%的纠正编辑。肝脏稳定编辑32使Z-A1AT水平降低80%以上，恢复正常肝脏表型。同时，在肺支气管肺泡灌洗液中实现89%的中性粒细胞弹性酶抑制。综上所述，双SORT LNP治疗为AATD等多器官疾病的长期基因组校正提供了一种有希望的方法。

据了解，α-1抗胰蛋白酶（A1AT）缺乏症（AATD）是由SERPINA1基因（PiZ等位基因）突变引起的，其中错误折叠的A1AT肝脏积聚导致肝损伤，肺部A1AT缺乏症由于中性粒细胞弹性酶活性不调节而导致肺气肿。碱基编辑为A1AT提供了一种潜在的治疗方法；然而，由于缺乏针对关键组织的双靶标递送系统，有效的治疗受到阻碍。

附：英文原文

Title: Dual SORT LNPs for multi-organ base editing

Author: Kim, Minjeong, Song, Eunice S., Chen, Joseph C., Chatterjee, Sumanta, Sun, Yehui, Lee, Sang M., Wu, Shiying, Patel, Priyanka, Tian, Zeru, Kantor, Ariel, Wustman, Brandon A., Lockhart, David J., Siegwart, Daniel J.

Issue&Volume: 2025-06-02

Abstract: Alpha-1 antitrypsin (A1AT) deficiency (AATD) is caused by a mutation in the SERPINA1 gene (PiZ allele), where misfolded A1AT liver accumulation leads to liver damage, and A1AT deficiency in the lungs results in emphysema due to unregulated neutrophil elastase activity. Base editing offers a potential cure for A1AT; however, effective treatment is hindered by the absence of dual-target delivery systems that can target key tissues. We developed Dual Selective ORgan-Targeting lipid nanoparticles (SORT LNPs) to deliver base editors to the liver and lungs. Dual SORT LNPs correct the PiZ mutation, achieving 40% correction editing in liver cells and 10% in lung AT2 cells. The liver maintains stable editing for 32weeks, reducing Z-A1AT levels by over 80% and restoring a normal liver phenotype. In parallel, 89% neutrophil elastase inhibition is achieved in lung bronchoalveolar lavage fluid. Taken together, Dual SORT LNP therapy offers a promising approach for long-lasting genome correction for multi-organ diseases such as AATD.

DOI: 10.1038/s41587-025-02675-z

Source: https://www.nature.com/articles/s41587-025-02675-z