Recirculating cardiac delivery of AAV2/1SERCA2a improves myocardial function in an experimental model of heart failure in large animals
Abstract
Abnormal excitation-contraction coupling is a key pathophysiologic component of heart failure (HF), and at a molecular level reduced expression of the sarcoplasmic reticulum (SR) Ca(2+) ATPase (SERCA2a) is a major contributor. Previous studies in small animals have suggested that restoration of SERCA function is beneficial in HF. Despite this promise, the means by which this information might be translated into potential clinical application remains uncertain. Using a recently established cardiac-directed recirculating method of gene delivery, we administered adeno-associated virus 2 (AAV2)/1SERCA2a to sheep with pacing-induced HF. We explored the effects of differing doses of AAV2/1SERCA2a (low 1 x 10(10) d.r.p.; medium 1 x 10(12) d.r.p. and high 1 x 10(13) d.r.p.) in conjunction with an intra-coronary delivery group (2.5 x 10(13) d.r.p.). At the end of the study, haemodynamic, echocardiographic, histopathologic and molecular biologic assessments were performed. Cardiac recirculation delivery of AAV2/1SERCA2a elicited a dose-dependent improvement in cardiac performance determined by left ventricular pressure analysis, (+d P/d t(max); low dose -220+/-70, P>0.05; medium dose 125+/-53, P<0.05; high dose 287+/-104, P<0.05) and echocardiographically (fractional shortening: low dose -3+/-2, P>0.05; medium dose 1+/-2, P>0.05; high dose 6.5+/-3.9, P<0.05). In addition to favourable haemodynamic effects, brain natriuretic peptide expression was reduced consistent with reversal of the HF molecular phenotype. In contrast, direct intra-coronary infusion did not elicit any effect on ventricular function. As such, AAV2/1SERCA2a elicits favourable functional and molecular actions when delivered in a mechanically targeted manner in an experimental model of HF. These observations lay a platform for potential clinical translation.
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Transduction of sheep myocardium with AAV vectors such as AAV-6 and AAV-2/1 has been successfully performed with techniques such as coronary infusion coupled with brief coronary and venous blockage and re-circulating systems.
“Transduction of sheep myocardium with AAV vectors (such as AAV-6 and AAV-2/1) have been successfully performed with techniques such as coronary infusion coupled with brief coronary and venous blockage (Beeri, et al., 2010) and re-circulating systems (Byrne, et al., 2008; J. D. White, et al., 2011) which target the myocardium directly and increase exposure time.”
From Small and large animal models in cardiac contraction research: advantages and disadvantages (2014) · cites this paper as Byrne, et al., 2008
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Self-citation
- Authors
- Byrne, M. J., Power, J. M., Preovolos, A., Mariani, J. A., Hajjar, R. J., & Kaye, D. M.
- Affiliations
- Baker Heart and Diabetes Institute (AU)
- Celladon Corporation (United States) (US)
- Corresponding author
- Byrne, M J
- Venue
- Gene Therapy
- Published
- 2008-07-24
- Volume
- 15
- Issue
- 23
- Pages
- 1550-1557
- ISSN
- 0969-7128 (ISSN-L)
- 1476-5462
- OpenAlex
- W1967089317
- Cited by
- 184
- References
- 25
- Citations by year
- 2026: 2 · 2025: 10 · 2024: 2 · 2023: 5 · 2022: 7 · 2021: 6 · 2020: 6 · 2019: 7 · 2018: 11 · 2017: 8 · 2016: 11 · 2015: 10 · 2014: 15 · 2013: 26 · 2012: 16
- FWCI
- 7.98
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Gene Therapy (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Celladon Corporation
- National Institutes of Health
- National Heart, Lung, and Blood Institute (R01HL071763, HL057263, HL-080498, HL 071763, R01HL080498, R01HL078691, HL 083156, R01HL083156)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- SERCA2a, adeno-associated virus type 2, heart failure, pacing-induced heart failure, sheep model, sarcoplasmic reticulum Ca2+-ATPase, excitation-contraction coupling, brain natriuretic peptide, myocardial function, dose-dependent effects
- MeSH terms
- Dependovirus, Animals, Cardiac Pacing, Artificial, Coronary Circulation, Dose-Response Relationship, Drug, Echocardiography, Genetic Vectors, Heart Failure, Liver, Lung, Myocardium, Random Allocation, RNA, Messenger, Sheep, Time, Transduction, Genetic, Genetic Therapy, Gene Expression, Polymerase Chain Reaction, Transgenes, Models, Animal, Sarcoplasmic Reticulum Calcium-Transporting ATPases
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