Targeted genome editing in vivo corrects a Dmd duplication restoring wild‐type dystrophin expression
| Autor: | Eleonora Maino, Matthew J. Rok, Tatianna Wai Ying Wong, Michelle Schneeweiss, Ori Scott, Sonia L Evagelou, Amanda Chiodo, Daria Wojtal, Lindsay K, Ronald D. Cohn, Evgueni A. Ivakine, Aiman Farheen, Samar Z Rizvi, Shagana Visuvanathan, Elzbieta Hyatt |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Duchenne muscular dystrophy Medicine (General) Computational biology QH426-470 medicine.disease_cause Article Dystrophin 03 medical and health sciences Mice 0302 clinical medicine R5-920 Genome editing duplication mutations Gene duplication medicine Genetics CRISPR Animals genome editing Musculoskeletal System CRISPR/Cas9 Gene Editing Mutation biology Cas9 Articles medicine.disease Muscular Dystrophy Duchenne 030104 developmental biology AAVs biology.protein Molecular Medicine Tandem exon duplication Genetics Gene Therapy & Genetic Disease CRISPR-Cas Systems 030217 neurology & neurosurgery RNA Guide Kinetoplastida |
| Zdroj: | EMBO Molecular Medicine, Vol 13, Iss 5, Pp n/a-n/a (2021) EMBO Molecular Medicine |
| ISSN: | 1757-4676 1757-4684 |
| Popis: | Tandem duplication mutations are increasingly found to be the direct cause of many rare heritable diseases, accounting for up to 10% of cases. Unfortunately, animal models recapitulating such mutations are scarce, limiting our ability to study them and develop genome editing therapies. Here, we describe the generation of a novel duplication mouse model, harboring a multi‐exonic tandem duplication in the Dmd gene which recapitulates a human mutation. Duplication correction of this mouse was achieved by implementing a single‐guide RNA (sgRNA) CRISPR/Cas9 approach. This strategy precisely removed a duplication mutation in vivo, restored full‐length dystrophin expression, and was accompanied by improvements in both histopathological and clinical phenotypes. We conclude that CRISPR/Cas9 represents a powerful tool to accurately model and treat tandem duplication mutations. Our findings will open new avenues of research for exploring the study and therapeutics of duplication disorders. Currently, no curative therapies exist for disorders caused by tandem duplication mutations. To address this critical need, CRISPR/Cas9‐mediated removal of a duplication mutation was demonstrated in‐vivo, leading to substantial improvement in disease phenotype in a tandem duplication DMD mouse model. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Plný text