麻省大学陈医学院王丹小组的一项最新研究提出了用于疾病不可知性AAV递送的工程UGA抑制tRNA基因。该项研究成果发表在2026年1月19日出版的《自然—生物技术》上。

小组证明了一个设计有转录调控元件的工程UGA-sup-tRNA基因可以有效地包装到rAAV中进行体内递送。单次给药可使两种不同溶酶体储存障碍的无主题模型恢复酶活性至正常水平的约10%。比较分析揭示了不同组织类型的sup-tRNA表达和氨基酰化模式的差异，这与增强的治疗效果有关。基于rAAV的药物和工程策略的应用扩大了sup-tRNA治疗的潜在治疗范围。

研究人员表示，抑制转移RNAs（sup-tRNA）具有以疾病不确定的方式拯救无义突变的潜力，是许多罕见和超罕见疾病的替代治疗方法。在所有人类致病性无义变异中，大约20%来自于将CGA精氨酸密码子转化为UGA终止密码子的C-to-T转换。虽然重组腺相关病毒（rAAV）已经成功地在体内传递了靶向UAG的sup-tRNA基因，但将这种方法扩展到靶向UAG的sup-tRNA基因，对rAAV载体的生产提出了独特的挑战。

附：英文原文

Title: An engineered UGA suppressor tRNA gene for disease-agnostic AAV delivery

Author: Xu, Mengyao, Liu, Hao, Wang, Jiaming, Vieira, Andre F. C., Zhou, Xuntao, Liu, Nan, Liang, Jialing, Du, Ailing, Chen, Xiupeng, Xing, Ruxiao, Yang, Yang, Gonzalez-Perez, Maria P., Kumar, Vikas, Wang, Dan

Issue&Volume: 2026-01-19

Abstract: Suppressor transfer RNAs (sup-tRNAs) have the potential to rescue nonsense mutations in a disease-agnostic manner and are an alternative therapeutic approach for many rare and ultrarare disorders. Among all human pathogenic nonsense variants, approximately 20% arise from C-to-T transitions that convert the CGA arginine codon into a UGA stop codon. While recombinant adeno-associated virus (rAAV) has been successfully used to deliver a UAG-targeting sup-tRNA gene in vivo, extending this approach to UGA-targeting sup-tRNA genes has posed unique challenges related to rAAV vector production. Here, we demonstrate that an engineered UGA-sup-tRNA gene, designed with transcriptional regulatory elements, can be efficiently packaged into rAAV for in vivo delivery. A single administration in mouse models of two distinct lysosomal storage disorders restores enzymatic activity to approximately 10% of normal levels. Comparative analysis reveals differential sup-tRNA expression and aminoacylation patterns across tissue types, which correlate with enhanced therapeutic effects. The applied rAAV-based agents and engineering strategies expand the potential therapeutic scope of sup-tRNA therapies.

DOI: 10.1038/s41587-025-02982-5

Source: https://www.nature.com/articles/s41587-025-02982-5