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通过RNAtrans-splicing拯救β-catenin:一种用于治疗CTNNB1-Haploinsufficiency疾病的新方法

Matea Maruna^1,2, Petra Sušjan-Leite¹, Maja Meško¹

¹Department of Synthetic Biology and Immunology, National Institute of Chemistry, Hajdrihova 19, 1000 Ljubljana, Slovenia.

Molecular therapy. Nucleic acids

|September 2, 2025

概括

这项研究引入了拼接酶媒介RNA转接 (SMaRT) 来恢复CTNNB1基因功能,为CTNNB1综合征提供了一种新的治疗方法. 这种不依赖突变的策略成功地纠正了细胞中的CTNNB1mRNA,显示出治疗这种神经发育障碍的前景.

科学领域:

分子生物学
基因治疗
神经发育障碍

背景情况:

CTNNB1综合征是CTNNB1基因功能丧失突变的结果,导致β-catenin缺乏和神经发育障碍.
由于CTNNB1基因的多种突变和剂量敏感性,现有的治疗策略面临挑战.

研究的目的:

引入和优化结合体介导RNA转接 (SMaRT) 作为CTNNB1综合征的突变独立治疗方法.
通过纠正CTNNB1mRNA恢复功能性β-catenin的产生.

主要方法:

使用分割黄色光蛋白记者系统设计和评估了针对CTNNB1内核的转接前RNA分子 (PTM).
采用反意义RNA来掩盖拼接调节元件,并结合了自我分裂的 ribozyme 来提高跨拼接效率.
在不同的表达条件下评估PTM有效性,包括CMV促进体驱动的表达,并对内源CTNNB1转录进行验证.

主要成果:

在mRNA和蛋白质水平上,优化的PTM显著提高了SMaRT的效率.
抗意义RNA和 ribozyme 的结合显著改善了转接结果.
通过CMV促进剂驱动的PTM表达表现出了最高的效率,成功纠正了内源CTNNB1mRNA.

结论:

这项研究为CTNNB1mRNA校正提供了SMaRT的首次应用和优化.
开发的SMaRT策略为CTNNB1综合征提供了一个有前途的,不依赖突变的治疗途径.
成功纠正内源性CTNNB1转录验证了这种方法在治疗神经发育障碍方面的生理相关性.

关键词:

CTNNB1综合征 MT:RNA/DNA编辑进行RNA疗法罕见的疾病核酶小反意义RNA 通过拼接

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