Hydrodynamic Limb Vein Injection of Adeno-Associated Virus Serotype 8 Vector Carrying Canine Myostatin Propeptide Gene into Normal Dogs Enhances Muscle Growth
| Autor: | Juan Li, Jianbin Li, Chunping Qiao, Zhenhua Yuan, Hui Zheng, Xiao Xiao, Joe N. Kornegay, Janet R. Bogan, Cheng Zhang, Dan Bogan |
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| Rok vydání: | 2009 |
| Předmět: |
Male
medicine.medical_specialty Genetic enhancement medicine.medical_treatment Genetic Vectors Myostatin Biology Muscle Development medicine.disease_cause Muscle hypertrophy Mice Dogs Internal medicine Scientific Papers Genetics medicine Animals Serotyping Muscle Skeletal Molecular Biology Adeno-associated virus Growth factor Gene Transfer Techniques Skeletal muscle Anatomy Dependovirus musculoskeletal system Blockade Endocrinology medicine.anatomical_structure Injections Intravenous biology.protein Molecular Medicine Peptides Blood vessel |
| Zdroj: | Human Gene Therapy. 20:1-10 |
| ISSN: | 1557-7422 1043-0342 |
| DOI: | 10.1089/hum.2008.135 |
| Popis: | Inhibition or blockade of myostatin, a negative growth factor of skeletal muscle, enhances muscle growth and therefore is considered a promising strategy for the treatment of muscle-wasting diseases such as the muscular dystrophies. Previously, we showed that myostatin blockade in both normal and dystrophin-deficient mdx mice by systemic delivery of the myostatin propeptide (MPRO) gene by an adeno-associated virus serotype 8 (AAV8) vector could enhance muscle growth and ameliorate dystrophic lesions. Here, we further investigate whether the muscle growth effect of myostatin blockade can be achieved in dogs by gene transfer. First, we cloned the canine MPRO gene, packaged it in the AAV8 vector, and showed robust muscle-enhancing effects after systemic delivery into neonatal mice. This vector was then further tested in two 3-month-old normal dogs (weighing 9.7 and 6.3 kg). The vector was delivered to one limb by hydrodynamic vein injection, and the contralateral limb served as a control. The delivery procedure was safe, without discernible adverse effects. AAV vector DNA and MPRO gene expression were detected by quantitative polymerase chain reaction, Western blotting, and immunofluorescence staining of muscle biopsies. Overexpression of MPRO resulted in enhanced muscle growth without a cytotoxic T lymphocytic immune response, as evidenced by larger myofibers in multiple muscles, increased muscle volume determined by magnetic resonance imaging, and the lack of CD4+ and CD8+ T cell infiltration in the vector-injected limbs. Our preliminary study thus supports further investigation of this therapeutic strategy in the dystrophin-deficient golden retriever muscular dystrophy dog model. |
| Databáze: | OpenAIRE |
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