Evaluation of vascular delivery methodologies to enhance rAAV6-mediated gene transfer to canine striated musculature
Open accessAbstract
A growing body of research supports the development of recombinant adeno-associated viral (rAAV) vectors for delivery of gene expression cassettes to striated musculature as a method of treating severe neuromuscular conditions. However, it is unclear whether delivery protocols that achieve extensive gene transfer in mice can be adapted to produce similarly extensive gene transfer in larger mammals and ultimately patients. Consequently, we sought to investigate methodological modifications that would facilitate rAAV-mediated gene transfer to the striated musculature of canines. A simple procedure incorporating acute (i) occlusion of limb blood flow, (ii) exsanguination via compression bandage, and (iii) vector "dwell" time of <20 minutes, markedly enhanced the transduction of limb muscles, compared with a simple bolus limb infusion of vector. A complementary method whereby vector was infused into the jugular vein led to efficient transduction of cardiomyocytes and to a lesser degree the diaphragm. Together these methods can be used to achieve transgene expression in heart, diaphragm, and limb muscles of juvenile dogs using rAAV6 vectors. These results establish that rAAV-mediated gene delivery is a viable approach to achieving systemic transduction of striated musculature in mammals approaching the dimensions of newborn humans.
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Gregorevic et al. were able to transduce canine myocardium by injecting recombinant AAV-6 intravenously in immune-suppressed animals.
“Gregorevic et al. were able to transduce canine myocardium by injecting recombinant AAV-6 intravenously in immune-suppressed animals (Gregorevic, et al., 2009).”
From Small and large animal models in cardiac contraction research: advantages and disadvantages (2014) · cites this paper as Gregorevic, et al., 2009
At least two reports suggest that transduction of canine myocardial tissue can be achieved intravenously.
“Although, at least two reports suggest that transduction of canine myocardial tissue can be achieved intravenously.”
From Small and large animal models in cardiac contraction research: advantages and disadvantages (2014) · cites this paper as Gregorevic, et al., 2009
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- Authors
- Gregorevic, P., Schultz, B. R., Allen, J. M., Halldorson, J. B., Blankinship, M. J., Meznarich, N. A., Kuhr, C. S., Doremus, C., Finn, E., Liggitt, D., & Chamberlain, J. S.
- Affiliations
- University of Washington (US)
- Corresponding author
- Chamberlain, Jeffrey S
- Venue
- Molecular Therapy
- Publisher
- Elsevier BV
- Published
- 2009-08
- Volume
- 17
- Issue
- 8
- Pages
- 1427-1433
- ISSN
- 1525-0016 (ISSN-L)
- PMC
- PMC2788962
- OpenAlex
- W1996773323
- Cited by
- 40
- References
- 35
- Citations by year
- 2023: 1 · 2021: 2 · 2019: 2 · 2018: 2 · 2017: 1 · 2016: 1 · 2015: 2 · 2014: 2 · 2013: 1 · 2012: 7
- FWCI
- 4.51
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular Therapy (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Muscular Dystrophy Association
- University of Washington
- Achievement Rewards for College Scientists Foundation
- Fondation ARC pour la Recherche sur le Cancer
- National Institutes of Health
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R37AR040864)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Health Sciences › Medicine › Genetics › Neurogenetic and Muscular Disorders Research
- Keywords
- rAAV vectors, canine model, exsanguination, diaphragm, neuromuscular disorders, transgene expression
- MeSH terms
- Dependovirus, Alkaline Phosphatase, Animals, Blood Vessels, Diaphragm, Dogs, Genetic Vectors, Hindlimb, Humans, Immunosuppression Therapy, Immunosuppressive Agents, Isoenzymes, Jugular Veins, Mycophenolic Acid, Myocardium, Cyclosporine, Gene Transfer Techniques, Muscle Fibers, Skeletal, Mice, GPI-Linked Proteins
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