Long-term robust myocardial transduction of the dog heart from a peripheral vein by adeno-associated virus serotype-8
Open accessAbstract
Molecular intervention using noninvasive myocardial gene transfer holds great promise for treating heart diseases. Robust cardiac transduction from peripheral vein injection has been achieved in rodents using adeno-associated virus (AAV) serotype-9 (AAV-9). However, a similar approach has failed to transduce the heart in dogs, a commonly used large animal model for heart diseases. To develop an effective noninvasive method to deliver exogenous genes to the dog heart, we employed an AAV-8 vector that expresses human placental alkaline phosphatase reporter gene under the transcriptional regulation of the Rous sarcoma virus promoter. Vectors were delivered to three neonatal dogs at the doses of 1.35×1014, 7.14×1014, and 9.06×1014 viral genome particles/kg body weight via the jugular vein. Transduction efficiency and overall safety were evaluated at 1.5, 2.5, and 12 months postinjection. AAV delivery was well tolerated and dog growth was normal. Blood chemistry and internal organ histology were unremarkable. Widespread skeletal muscle transduction was observed in all dogs without T-cell infiltration. Encouragingly, whole heart myocardial transduction was achieved in two dogs that received higher doses and cardiac expression lasted for at least 1 year. In summary, peripheral vein AAV-8 injection may represent a simple heart gene transfer method in large mammals. Further optimization of this gene delivery strategy may open the door for a readily applicable gene therapy method to treat many heart diseases. Pan and colleagues administer, via the jugular vein, adeno-associated virus serotype 8 (AAV8) vector expressing a human placental alkaline phosphatase reporter gene under the control of the Rous sarcoma virus promoter to three neonatal dogs at doses of 1.35 × 1014, 7.14 × 1014, and 9.06 × 1014 viral genome particles/kg body weight. Using this approach, they observe widespread skeletal muscle transduction in all dogs without T cell infiltration. Interestingly, whole heart myocardial transduction was achieved in the two dogs that received the highest doses, and this expression lasted for at least 1 year.
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Recombinant AAV-8 was able to transduce canine myocardium up to 12 months post-injection when injected at high doses intravenously in neonatal canines.
“recombinant AAV-8 was able to transduce canine myocardium up to 12 months post-injection when it was injected at high doses intravenously in neonatal canines. (Pan, et al., 2013).”
From Small and large animal models in cardiac contraction research: advantages and disadvantages (2014) · cites this paper as Pan, et al., 2013
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 Pan, et al., 2013
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- Authors
- Pan, X., Yue, Y., Zhang, K., Lostal, W., Shin, J.-H., & Duan, D.
- Affiliations
- University of Missouri (US)
- Genethon (France) (FR)
- Pusan National University Yangsan Hospital (KR)
- Corresponding author
- Duan, Dongsheng
- Venue
- Human Gene Therapy
- Publisher
- SAGE Publications
- Published
- 2013-06
- Volume
- 24
- Issue
- 6
- Pages
- 584-594
- ISSN
- 1043-0342 (ISSN-L)
- 1557-7422
- PMC
- PMC3689160
- OpenAlex
- W1987049254
- Cited by
- 30
- References
- 33
- Citations by year
- 2026: 1 · 2025: 2 · 2023: 2 · 2022: 1 · 2021: 1 · 2020: 1 · 2019: 2 · 2018: 1 · 2017: 4 · 2016: 3 · 2015: 8 · 2014: 3 · 2013: 1
- FWCI
- 3.31
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Human Gene Therapy (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Muscular Dystrophy Association
- National Institutes of Health
- National Heart, Lung, and Blood Institute (R01HL091883, HL-91883)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR49419, R01AR049419)
- 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 › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Keywords
- AAV8, canine model, Rous sarcoma virus promoter, skeletal muscle transduction, T cell infiltration
- MeSH terms
- Dependovirus, Animals, Animals, Newborn, Dogs, Female, Humans, Injections, Intravenous, Jugular Veins, Male, Myocardium, Serotyping, T-Lymphocytes, Time Factors, Transduction, Genetic, Genome, Viral, Muscle, Skeletal
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