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Muscle Function Recovery in Golden Retriever Muscular Dystrophy After AAV1-U7 Exon Skipping
- Source :
- Molecular Therapy. 20(11):2120-2133
- Publication Year :
- 2012
- Publisher :
- Elsevier BV, 2012.
-
Abstract
- Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder resulting from lesions of the gene encoding dystrophin. These usually consist of large genomic deletions, the extents of which are not correlated with the severity of the phenotype. Out-of-frame deletions give rise to dystrophin deficiency and severe DMD phenotypes, while internal deletions that produce in-frame mRNAs encoding truncated proteins can lead to a milder myopathy known as Becker muscular dystrophy (BMD). Widespread restoration of dystrophin expression via adeno-associated virus (AAV)-mediated exon skipping has been successfully demonstrated in the mdx mouse model and in cardiac muscle after percutaneous transendocardial delivery in the golden retriever muscular dystrophy dog (GRMD) model. Here, a set of optimized U7snRNAs carrying antisense sequences designed to rescue dystrophin were delivered into GRMD skeletal muscles by AAV1 gene transfer using intramuscular injection or forelimb perfusion. We show sustained correction of the dystrophic phenotype in extended muscle areas and partial recovery of muscle strength. Muscle architecture was improved and fibers displayed the hallmarks of mature and functional units. A 5-year follow-up ruled out immune rejection drawbacks but showed a progressive decline in the number of corrected muscle fibers, likely due to the persistence of a mild dystrophic process such as occurs in BMD phenotypes. Although AAV-mediated exon skipping was shown safe and efficient to rescue a truncated dystrophin, it appears that recurrent treatments would be required to maintain therapeutic benefit ahead of the progression of the disease.
- Subjects :
- musculoskeletal diseases
medicine.medical_specialty
mdx mouse
congenital, hereditary, and neonatal diseases and abnormalities
Transcription, Genetic
Utrophin
Duchenne muscular dystrophy
Genetic Vectors
Molecular Sequence Data
Muscle Fibers, Skeletal
Biology
Injections, Intramuscular
Dystrophin
Dogs
Internal medicine
RNA, Small Nuclear
Forelimb
Drug Discovery
medicine
Genetics
Animals
Muscle Strength
Muscular dystrophy
Myopathy
Muscle, Skeletal
Molecular Biology
Pharmacology
Base Sequence
Exons
Genetic Therapy
Dependovirus
Muscular Dystrophy, Animal
medicine.disease
Exon skipping
Alternative Splicing
Endocrinology
biology.protein
Molecular Medicine
Calcium
Original Article
medicine.symptom
ITGA7
Muscle Contraction
Oligoribonucleotides, Antisense
Subjects
Details
- ISSN :
- 15250016
- Volume :
- 20
- Issue :
- 11
- Database :
- OpenAIRE
- Journal :
- Molecular Therapy
- Accession number :
- edsair.doi.dedup.....0e9c470871ffc1cdfe1331779839db2e
- Full Text :
- https://doi.org/10.1038/mt.2012.181