设计的 U7 snRNA 抑制 DUX4 表达并改善 DUX4 过表达细胞和 FSHD 患者肌管中 FSHD 相关的结果,Molecular Therapy - Nucleic Acids

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设计的 U7 snRNA 抑制 DUX4 表达并改善 DUX4 过表达细胞和 FSHD 患者肌管中 FSHD 相关的结果
Molecular Therapy - Nucleic Acids ( IF 6.5 ) Pub Date : 2020-12-10 , DOI: 10.1016/j.omtn.2020.12.004
Afrooz Rashnonejad , Gholamhossein Amini-Chermahini , Noah K. Taylor , Nicolas Wein , Scott Q. Harper

面肩肱型肌营养不良症 (FSHD) 是由表观遗传变化引起的，这种变化解除了肌肉中基因的抑制。全长 DUX4 蛋白会导致细胞死亡和肌肉毒性，因此我们假设 FSHD 疗法应集中于抑制全长表达。在这项研究中，我们开发了一种使用 U7-小核 RNA (snRNA) 反义表达盒（称为 U7-asDUX4）实现抑制的策略。这些非编码 RNA 旨在通过掩蔽起始密码子、剪接位点或多腺苷酸化信号来抑制全长前 mRNA 的产生或成熟。在此过程中，U7-asDUX4 snRNA 的运作方式与反义寡核苷酸类似。然而，与寡核苷酸相比，寡核苷酸受到肌肉吸收不良和需要终生重复给药的限制，U7-asDUX4 snRNA 可以包装在促肌基因治疗载体中，并且在递送至有丝分裂后细胞时可能只需要单次给药。我们测试了几种可减少表达并改善 DUX4 相关结果的 U7-asDUX4。通过 U7-snRNA 抑制表达可能是 FSHD 的一种新的前瞻性基因治疗方法，或者与其他策略（如 RNAi 治疗）结合使用，以最大限度地提高 FSHD 个体的沉默效果。

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Designed U7 snRNAs inhibit DUX4 expression and improve FSHD-associated outcomes in DUX4 overexpressing cells and FSHD patient myotubes

Facioscapulohumeral muscular dystrophy (FSHD) arises from epigenetic changes that de-repress the gene in muscle. The full-length DUX4 protein causes cell death and muscle toxicity, and therefore we hypothesize that FSHD therapies should center on inhibiting full-length expression. In this study, we developed a strategy to accomplish inhibition using U7-small nuclear RNA (snRNA) antisense expression cassettes (called U7-asDUX4). These non-coding RNAs were designed to inhibit production or maturation of the full-length pre-mRNA by masking the start codon, splice sites, or polyadenylation signal. In so doing, U7-asDUX4 snRNAs operate similarly to antisense oligonucleotides. However, in contrast to oligonucleotides, which are limited by poor uptake in muscle and a requirement for lifelong repeated dosing, U7-asDUX4 snRNAs can be packaged within myotropic gene therapy vectors and may require only a single administration when delivered to post-mitotic cells . We tested several U7-asDUX4s that reduced expression and improved DUX4-associated outcomes. Inhibition of expression via U7-snRNAs could be a new prospective gene therapy approach for FSHD or be used in combination with other strategies, like RNAi therapy, to maximize silencing in individuals with FSHD.

更新日期：2020-12-10

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