Journal
MOLECULAR THERAPY
Volume 25, Issue 11, Pages 2561-2572Publisher
CELL PRESS
DOI: 10.1016/j.ymthe.2017.07.014
Keywords
-
Categories
Funding
- Parent Project Muscular Dystrophy USA
- Canadian Institutes of Health Research [FRN134134, 132574]
- Friends of Garrett Cumming Research Funds
- HM Toupin Neurological Science Research Funds
- Muscular Dystrophy Canada
- Canada Foundation for Innovation [30819]
- Alberta Enterprise and Advanced Education
- Women and Children's Health Research Institute
- Association Francaise contre les Myopathies
- Alberta Innovates - Health Solutions (Summer Studentship Award)
- NIH [5U54HD053177, K26OD011171, P50AR060836-01]
- US Department of Defense [W81XWH-05-1-0616, W81XWH-11-1-0782]
- NIH NIAMS [5T32AR056993]
- Japan Society for the Promotion of Science
- University of Alberta Faculty of Medicine and Dentistry
- Alberta Innovates [201500096] Funding Source: researchfish
Ask authors/readers for more resources
Duchenne muscular dystrophy (DMD), the most common lethal genetic disorder, is caused by mutations in the dystrophin (DMD) gene. Exon skipping is a therapeutic approach that uses antisense oligonucleotides (AOs) to modulate splicing and restore the reading frame, leading to truncated, yet functional protein expression. In 2016, the US Food and Drug Administration (FDA) conditionally approved the first phosphorodiamidate morpholino oligomer (morpholino)-based AO drug, eteplirsen, developed for DMD exon 51 skipping. Eteplirsen remains controversial with insufficient evidence of its therapeutic effect in patients. We recently developed an in silico tool to design antisense morpholino sequences for exon skipping. Here, we designed morpholino AOs targeting DMD exon 51 using the in silico tool and quantitatively evaluated the effects in immortalized DMD muscle cells in vitro. To our surprise, most of the newly designed morpholinos induced exon 51 skipping more efficiently compared with the eteplirsen sequence. The efficacy of exon 51 skipping and rescue of dystrophin protein expression were increased by up to more than 12-fold and 7-fold, respectively, compared with the eteplirsen sequence. Significant in vivo efficacy of the most effective morpholino, determined in vitro, was confirmed in mice carrying the human DMD gene. These findings underscore the importance of AO sequence optimization for exon skipping.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available