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通过调节伪埃克森拼接模式来调节PCCA基因表达,以在propionic acidemia中拯救酶活性

Ulrika Simone Spangsberg Petersen¹, Maja Dembic^1,2,3, Ainhoa Martínez-Pizarro⁴

¹Department of Biochemistry and Molecular Biology and the Villum Center for Bioanalytical Sciences, University of Southern Denmark, 5230 Odense M, Denmark.

Molecular therapy. Nucleic acids

|January 11, 2024

概括

在PCCA中深层的intronic变异激活了一个伪exon,导致propionic acidemia. 反感性寡核酸可以恢复正常的剪接和酶活性,为这种代谢障碍提供潜在的治疗策略.

科学领域:

分子生物学分子生物学
遗传学遗传学是一个
生物化学生化学

背景情况:

伪exons是通过深层intronic变异激活的内基序列,导致异常的mRNA拼接和基因表达干扰.
由于PCCA基因变异c.1285-1416A>G激活了伪外显子,导致由于propionyl-CoA核糖酶缺乏而导致酸血症.

研究的目的:

为了描述PCCA中的致病性伪子激活事件.
调查hNRNP A1在伪子抑制中的作用.
开发一种治疗酸血症的治疗策略,使用拼接切换反感性寡核酸.

主要方法:

对PCCA伪子激活机制的详细描述.
鉴定hNRNP A1作为一个关键的抑制剂的伪子的含有.
拼接切换反感性寡核酸的应用,以恢复患者纤维细胞和CRISPR编辑细胞模型的正常拼接.
在细胞模型中对酶活性救援的评估.

主要成果:

这种PCCA c.1285-1416A>G变异破坏了hNRNP A1结合式声器,并产生了拼接增强器.
拼接切换反感性寡核酸成功地恢复了正常的PCCA拼接,并挽救了酶活性.
阻断野生类型伪埃克松的含量增加了PCCA和PCCB蛋白质水平和酶活性.
治疗策略在患有PCCA和PCCB误解变异的患者纤维细胞中显示出有效性.

结论:

通过深度内部变化的伪埃克松激活是 propionic acidemia 的一种机制.
用反感性寡核酸向伪埃克松纳入是一种可行的治疗策略.
这种方法有可能提高PCCA和PCCB水平,为酸血症提供治疗.

关键词:

MT:寡核酸:治疗方法和应用.这是PCCA的PCCA.核基因输出的有针对性的增加 (TANGO)一个神秘的拼接.代谢障碍代谢障碍是一种代谢障碍.在mRNA前拼接.酸血症酸血症尼尔-CoA碳氧化酶是一种这是一个假的exonon.拼接切换的反意义寡核酸.

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