Journal article
Injection of a recombinant AAV serotype 2 into canine skeletal muscles evokes strong immune responses against transgene products
Gene Therapy, Vol.14(17), pp.1249-1260
2007
Abstract
Using murine models, we have previously demonstrated that recombinant adeno-associated virus (rAAV)-mediated microdystrophin gene transfer is a promising approach to treatment of Duchenne muscular dystrophy (DMD). To examine further therapeutic effects and the safety issue of rAAV-mediated microdystrophin gene transfer using larger animal models, such as dystrophic dog models, we first investigated transduction efficiency of rAAV in wild-type canine muscle cells, and found that rAAV2 encoding β-galactosidase effectively transduces canine primary myotubes in vitro. Subsequent rAAV2 transfer into skeletal muscles of normal dogs, however, resulted in low and transient expression of β-galactosidase together with intense cellular infiltrations in vivo, where cellular and humoral immune responses were remarkably activated. In contrast, rAAV2 expressing no transgene elicited no cellular infiltrations. Co-administration of immunosuppressants, cyclosporine and mycophenolate mofetil could partially improve rAAV2 transduction. Collectively, these results suggest that immune responses against the transgene product caused cellular infiltration and eliminated transduced myofibers in dogs. Furthermore, in vitro interferon-γ release assay showed that canine splenocytes respond to immunogens or mitogens more susceptibly than murine ones. Our results emphasize the importance to scrutinize the immune responses to AAV vectors in larger animal models before applying rAAV-mediated gene therapy to DMD patients.
Details
- Title
- Injection of a recombinant AAV serotype 2 into canine skeletal muscles evokes strong immune responses against transgene products
- Authors/Creators
- K. Yuasa (Author/Creator) - National Center of Neurology and PsychiatryM. Yoshimura (Author/Creator) - National Center of Neurology and PsychiatryN. Urasawa (Author/Creator) - National Center of Neurology and PsychiatryS. Ohshima (Author/Creator) - National Center of Neurology and PsychiatryJ.M. Howell (Author/Creator) - Centre for Neuromuscular and Neurological DisordersA. Nakamura (Author/Creator) - National Center of Neurology and PsychiatryT. Hijikata (Author/Creator) - Musashino UniversityY. Miyagoe-Suzuki (Author/Creator) - National Center of Neurology and PsychiatryS. Takeda (Author/Creator) - National Center of Neurology and Psychiatry
- Publication Details
- Gene Therapy, Vol.14(17), pp.1249-1260
- Publisher
- Nature Publishing Group
- Identifiers
- 991005540116207891
- Copyright
- © 2007 Nature Publishing Group
- Murdoch Affiliation
- School of Veterinary and Biomedical Sciences
- Language
- English
- Resource Type
- Journal article
UN Sustainable Development Goals (SDGs)
This output has contributed to the advancement of the following goals:
Source: InCites
Metrics
19 Record Views
InCites Highlights
These are selected metrics from InCites Benchmarking & Analytics tool, related to this output
- Collaboration types
- Domestic collaboration
- International collaboration
- Citation topics
- 1 Clinical & Life Sciences
- 1.161 Virology - Identification & Sequencing
- 1.161.479 Oncolytic Viruses
- Web Of Science research areas
- Biochemistry & Molecular Biology
- Biotechnology & Applied Microbiology
- Genetics & Heredity
- Medicine, Research & Experimental
- ESI research areas
- Molecular Biology & Genetics