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替代拼接的治疗向,由致命的非编码结构变异引起的X链接的 dystonia parkinsonism X链接的 dystonia parkinsonism

Rachita Yadav^1,2,3,4,5, Christine A Vaine^2,5, Aloysius Domingo^1,2,3,4,5

¹Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.

medRxiv : the preprint server for health sciences

|November 24, 2025

概括

研究人员发现了一种新型的SINE-VNTR-Alu插入,导致X链接的迪斯顿症-帕金森症 (XDP),并开发了反感性寡核化物 (ASO) 来纠正异常拼接,为菲律宾患者提供潜在的精确治疗.

科学领域:

神经遗传学神经遗传学
分子生物学分子生物学
基因组医学是基因组医学.

背景情况:

链接到X的迪斯顿症-帕金森症 (XDP) 是一种罕见的,致命的神经退行性疾病,影响菲律宾男性.
菲律宾本土的一种特定的创始人哈普洛型与XDP有关.
这种疾病表现为 dystonia 和 parkinsonism 的症状.

研究的目的:

阐明XDP背后的分子机制.
开发和评估XDP的精密治疗策略.
验证患者衍生的神经干细胞 (NSC) 作为XDP研究的模型.

主要方法:

使用患者特异性纤维细胞和神经干细胞 (NSC) 进行建模.
采用基于CRISPR的基因编辑来切除TAF1.1中的SVA插入.
开发了一个功能性基因组学平台来选针对SVA插入的反意义寡核酸 (ASO).
在神经元模型和死后大脑样本上进行了转录组分析.

主要成果:

在TAF1内子32中发现了一种新的SINE-VNTR-Alu (SVA) 移动元素插入,作为XDP中神秘替代拼接的原因.
对SVA插入的CRISPR切除纠正了异常拼接,并在NSC中部分恢复了基因表达.
选了80个ASO,确定了改善XDP特定异常拼接的领先候选人.
两个领先的ASO证明了XDP特异差异表达基因 (DEGs) 的显著救援,恢复了分子功能.

结论:

来自患者的NSC准确地反映了在大脑组织中发现的XDP的分子标志.
基于CRISPR的校正为XDP治疗开发提供了概念验证.
对菲律宾XDP患者来说,反意义寡核酸 (ASO) 是一种可处理的治疗方法.
这项研究建立了一个可扩展的精确治疗平台,用于使用功能基因组学的罕见遗传疾病.

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