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CRISPR-Cas9 correction in the DMD mouse model is accompanied by upregulation of Dp71f proteinстатья
- Авторы: Egorova Tatiana V., Polikarpova Anna V., Vassilieva Svetlana G., Dzhenkova Marina A., Savchenko Irina M., Velyaev Oleg A., Shmidt Anna A., Soldatov Vladislav O., Pokrovskii Mikhail V., Deykin Alexey V., Bardina Maryana V.
- Журнал: Molecular Therapy - Methods & Clinical Development
- Том: 30
- Год издания: 2023
- Издательство: Nature Publishing Group
- Местоположение издательства: United Kingdom
- Первая страница: 161
- Последняя страница: 180
- DOI: 10.1016/j.omtm.2023.06.006
- Аннотация: Duchenne muscular dystrophy (DMD) is a severe hereditary disease caused by a deficiency in the dystrophin protein. The most frequent types of disease-causing mutations in the DMD gene are frameshift deletions of one or more exons. Precision genome editing systems such as CRISPR-Cas9 have shown potential to restore open reading frames in numerous animal studies. Here, we applied an AAV-CRISPR double-cut strategy to correct a mutation in the DMD mouse model with exon 8–34 deletion, encompassing the N-terminal actin-binding domain. We report successful excision of the 100-kb genomic sequence, which includes exons 6 and 7, and partial improvement in cardiorespiratory function. While corrected mRNA was abundant in muscle tissues, only a low level of truncated dystrophin was produced, possibly because of protein instability. Furthermore, CRISPR-Cas9-mediated genome editing upregulated the Dp71f dystrophin isoform on the sarcolemma. Given the previously reported Dp71-associated muscle pathology, our results question the applicability of genome editing strategies for some DMD patients with N-terminal mutations. The safety and efficacy of CRISPR-Cas9 constructs require rigorous investigation in patient-specific animal models.
- Добавил в систему: Бардина Марьяна Владимировна