Autor: |
Afrooz Rashnonejad, Gholamhossein Amini-Chermahini, Noah K. Taylor, Nicolas Wein, Scott Q. Harper |
Jazyk: |
angličtina |
Rok vydání: |
2021 |
Předmět: |
|
Zdroj: |
Molecular Therapy: Nucleic Acids, Vol 23, Iss , Pp 476-486 (2021) |
Druh dokumentu: |
article |
ISSN: |
2162-2531 |
DOI: |
10.1016/j.omtn.2020.12.004 |
Popis: |
Facioscapulohumeral muscular dystrophy (FSHD) arises from epigenetic changes that de-repress the DUX4 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 DUX4 expression. In this study, we developed a strategy to accomplish DUX4 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 DUX4 pre-mRNA by masking the DUX4 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 in vivo. We tested several U7-asDUX4s that reduced DUX4 expression in vitro and improved DUX4-associated outcomes. Inhibition of DUX4 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 DUX4 silencing in individuals with FSHD. |
Databáze: |
Directory of Open Access Journals |
Externí odkaz: |
|