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Long-Term Systemic Myostatin Inhibition via Liver-Targeted Gene Transfer in Golden Retriever Muscular Dystrophy
- Source :
- Human Gene Therapy. 22:1499-1509
- Publication Year :
- 2011
- Publisher :
- Mary Ann Liebert Inc, 2011.
-
Abstract
- Duchenne muscular dystrophy (DMD) is a lethal, X-linked recessive disease affecting 1 in 3,500 newborn boys for which there is no effective treatment or cure. One novel strategy that has therapeutic potential for DMD is inhibition of myostatin, a negative regulator of skeletal muscle mass that may also promote fibrosis. Therefore, our goal in this study was to evaluate systemic myostatin inhibition in the golden retriever model of DMD (GRMD). GRMD canines underwent liver-directed gene transfer of a self-complementary adeno-associated virus type 8 vector designed to express a secreted dominant-negative myostatin peptide (n = 4) and were compared with age-matched, untreated GRMD controls (n = 3). Dogs were followed with serial magnetic resonance imaging (MRI) for 13 months to assess cross-sectional area and volume of skeletal muscle, then euthanized so that tissue could be harvested for morphological and histological analysis. We found that systemic myostatin inhibition resulted in increased muscle mass in GRMD dogs as assessed by MRI and confirmed at tissue harvest. We also found that hypertrophy of type IIA fibers was largely responsible for the increased muscle mass and that reductions in serum creatine kinase and muscle fibrosis were associated with long-term myostatin inhibition in GRMD. This is the first report describing the effects of long-term, systemic myostatin inhibition in a large-animal model of DMD, and we believe that the simple and effective nature of our liver-directed gene-transfer strategy makes it an ideal candidate for evaluation as a novel therapeutic approach for DMD patients.
- Subjects :
- medicine.medical_specialty
Duchenne muscular dystrophy
Blotting, Western
Genetic Vectors
Green Fluorescent Proteins
Golden Retriever
Myostatin
Real-Time Polymerase Chain Reaction
Dogs
Fibrosis
Internal medicine
Genetics
medicine
Animals
RNA, Messenger
Muscular dystrophy
Muscle, Skeletal
Creatine Kinase
Molecular Biology
Research Articles
biology
Skeletal muscle
Dependovirus
Muscular Dystrophy, Animal
musculoskeletal system
medicine.disease
Magnetic Resonance Imaging
STAT Transcription Factors
medicine.anatomical_structure
Real-time polymerase chain reaction
Endocrinology
Liver
biology.protein
Molecular Medicine
Creatine kinase
Subjects
Details
- ISSN :
- 15577422 and 10430342
- Volume :
- 22
- Database :
- OpenAIRE
- Journal :
- Human Gene Therapy
- Accession number :
- edsair.doi.dedup.....b4c14c397112e5326e18467627c75226