近日，美国密苏里大学Scott T. Younger及其研究小组实现快速且可扩展的个性化ASO筛选在患者来源的类器官中的应用。相关论文于2025年1月22日在线发表在《自然》杂志上。

研究人员描述了一个可扩展的平台，用于生成患者来源的细胞模型，并展示了这些个性化模型可用于患者特异性反义寡核苷酸（ASO）的临床前评估。研究人员描述了将ASO递送到患者来源类器官模型的方案，并确认了来自一名患有杜氏肌营养不良症（DMD）的患者的心脏类器官中，具有编码肌萎缩蛋白（DMD）基因结构性缺失的疾病相关表型得到了逆转，该缺失适用于现有的ASO治疗药物。

此外，研究人员为另外两名患有DMD（兄妹）的患者设计了新的患者特异性ASO，这些患者具有DMD基因中的深 内含子变异，导致出现一个新的剪接接受位点，内含子外显子加入以及转录提前终止。研究人员展示了通过患者特异性ASO治疗患者来源的心脏类器官，能够恢复DMD表达并逆转疾病相关表型。研究人员概述的方法为个性化ASO治疗的设计和临床前评估提供了基础，为广泛罕见疾病的治疗提供了加速路径。

据介绍，个性化ASO在治疗罕见遗传病方面取得了积极的成果。随着临床测序技术的不断进步，识别携带致病遗传变异且适合采用这种治疗策略的罕见疾病患者的能力可能会得到改善。

附：英文原文

Title: Rapid and scalable personalized ASO screening in patient-derived organoids

Author: Means, John C., Martinez-Bengochea, Anabel L., Louiselle, Daniel A., Nemechek, Jacqelyn M., Perry, John M., Farrow, Emily G., Pastinen, Tomi, Younger, Scott T.

Issue&Volume: 2025-01-22

Abstract: Personalized antisense oligonucleotides (ASOs) have achieved positive results in the treatment of rare genetic disease1. As clinical sequencing technologies continue to advance, the ability to identify patients with rare disease harbouring pathogenic genetic variants amenable to this therapeutic strategy will probably improve. Here we describe a scalable platform for generating patient-derived cellular models and demonstrate that these personalized models can be used for preclinical evaluation of patient-specific ASOs. We describe protocols for delivery of ASOs to patient-derived organoid models and confirm reversal of disease-associated phenotypes in cardiac organoids derived from a patient with Duchenne muscular dystrophy (DMD) with a structural deletion in the gene encoding dystrophin (DMD) that is amenable to treatment with existing ASO therapeutics. Furthermore, we designed novel patient-specific ASOs for two additional patients with DMD (siblings) with a deep intronic variant in the DMD gene that gives rise to a novel splice acceptor site, incorporation of a cryptic exon and premature transcript termination. We showed that treatment of patient-derived cardiac organoids with patient-specific ASOs results in restoration of DMD expression and reversal of disease-associated phenotypes. The approach outlined here provides the foundation for an expedited path towards the design and preclinical evaluation of personalized ASO therapeutics for a broad range of rare diseases.

DOI: 10.1038/s41586-024-08462-1

Source: https://www.nature.com/articles/s41586-024-08462-1