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对抗拼接纠正抗感性寡核酸的染色质效应,提高其在脊髓肌肉缩中的治疗效果

Luciano E Marasco¹, Gwendal Dujardin², Rui Sousa-Luís³

¹Universidad de Buenos Aires (UBA), Facultad de Ciencias Exactas y Naturales, Departamento de Fisiología, Biología Molecular y Celular and CONICET-UBA, Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE), 1428 Buenos Aires, Argentina.

|June 10, 2022

概括

通过将抗意义寡核酸 (ASO) 与VPA结合使用,改善了脊髓肌缩 (SMA) 的治疗. 这种协同作用通过克服ASO诱导的障碍来提高SMA小鼠的SMN蛋白水平和运动功能.

科学领域:

遗传学
神经科学
分子生物学

背景情况:

脊柱肌缩 (SMA) 是一种严重的运动神经元疾病,由SMN1基因突变引起.
该SMN2基因部分补偿,但主要跳过第7个外基因 (E7),限制了功能性SMN蛋白质的产生.
目前的治疗方法如nusinersen使用反意义寡核酸 (ASO) 来增加E7的含量.

研究的目的:

研究类似于nusinersen的ASO和VPA对SMN2基因表达和SMA治疗的协同作用.
为了阐明组合疗法的分子机制.

主要方法:

在SMA小鼠模型中使用了类似nusinersen的ASO和VPA (胰岛素脱乙酶抑制剂).
分析了SMN2基因上的E7含量,SMN蛋白水平和染色质修饰 (H3K9me2).
评估了生长,生存和神经肌肉功能的改善.

主要成果:

仅ASO就增加了E7的含量,但矛盾的是,它还在SMN2上诱导了抑制性H3K9me2标记,阻碍了延长.
通过促进转录延长,增强E7含量,VPA抵消了这些表观遗传障碍.
在SMA小鼠中,ASO和VPA联合治疗协同增强了SMN表达,生长,生存和神经肌肉功能.

结论:

VPA对抗ASO诱导的SMN2表观遗传沉默,从而提高治疗效果.
结合ASO和VPA疗法为治疗脊柱肌肉缩提供了强有力的协同方法.
这种策略克服了ASO单一治疗的局限性,通过解决拼接和基于染色素的调节.

关键词:

替代拼接抗意义的寡核酸治疗染色体基因组乙化脊柱肌肉缩转录延长

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