Cardiac-targeted RNA interference mediated by an AAV9 vector improves cardiac function in coxsackievirus B3 cardiomyopathy
Abstract
RNA interference (RNAi) has potential to be a novel therapeutic strategy in diverse areas of medicine. In this paper, we report on targeted RNAi for the treatment of a viral cardiomyopathy, which is a major cause of sudden cardiac death or terminal heart failure in children and young adults. RNAi therapy employs small regulatory RNAs to achieve its effect, but in vivo use of synthetic small interfering RNAs is limited by instability in plasma and low transfer into target cells. We instead evaluated an RNAi strategy using short hairpin RNA (shRdRp) directed at the RNA polymerase (RdRP) of coxsackievirus B3 (CoxB3) in HeLa cells, primary rat cardiomyocytes (PNCMs) and CoxB3-infected mice in vivo. A conventional AAV2 vector expressing shRdRp protected HeLa against virus-induced death, but this vector type was unable to transduce PNCMs. In contrast, an analogous pseudotyped AAV2.6 vector was protective also in PNCMs and reduced virus replication by >3 log10 steps. Finally, we evaluated the intravenous treatment of mice with an AAV2.9-shRdRp vector because AAV9 carries the most cardiotropic AAV capsid currently known for in vivo use. Mice with CoxB3 cardiomyopathy had disturbed left ventricular (LV) function with impaired parameters of contractility (dP/dtmax = 3,006 +/- 287 vs. 7,482 +/- 487 mmHg/s, p < 0.01) and diastolic relaxation (dP/dtmin = -2,224 +/- 195 vs. -6,456 +/- 356 mmHg/s, p < 0.01 and Tau = 16.2 +/- 1.1 vs. 10.7 +/- 0.6 ms, p < 0.01) compared to control mice. AAV2.…
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AAV9 binds to terminal galactose and shows efficient transduction in CNS, eye, cardiac and skeletal muscle, and liver.
“Another validated vector with broad tropism is AAV9, binding to terminal galactose and showing efficient transduction in CNS, eye, cardiac and skeletal muscle, and liver [50–53].”
From Designing and optimizing AAV-mediated gene therapy for neurodegenerative diseases: from bench to bedside (2024) · cites this paper as [52]
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- Authors
- Fechner, H., Sipo, I., Westermann, D., Pinkert, S., Wang, X., Suckau, L., Kurreck, J., Zeichhardt, H., Müller, O., Vetter, R., Erdmann, V., Tschope, C., & Poller, W.
- Affiliations
- Stiftung Charité (DE)
- Charité – Universitätsmedizin Berlin (DE)
- Freie Universität Berlin (DE)
- Heidelberg University (DE)
- Corresponding author
- Poller, Wolfgang
- ORCID
- Venue
- Journal of Molecular Medicine
- Published
- 2008-06-12
- Volume
- 86
- Issue
- 9
- Pages
- 987-997
- ISSN
- 0946-2716 (ISSN-L)
- 1432-1440
- OpenAlex
- W1979873003
- Cited by
- 79
- References
- 31
- Citations by year
- 2025: 1 · 2024: 2 · 2023: 3 · 2022: 2 · 2021: 1 · 2020: 1 · 2019: 5 · 2018: 3 · 2017: 5 · 2016: 3 · 2015: 6 · 2014: 7 · 2013: 6 · 2012: 4
- FWCI
- 5.71
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Journal of Molecular Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- Virginia Agricultural Experiment Station, Virginia Polytechnic Institute and State University
- 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 › Viral Infections and Immunology Research
- Keywords
- RNA interference, coxsackievirus B3, viral cardiomyopathy, AAV9 vector, shRNA, RNA polymerase, cardiomyocytes, cardiac function, viral replication, gene therapy, heart failure, sudden cardiac death, diastolic dysfunction, left ventricular contractility
- MeSH terms
- Dependovirus, Adult, Animals, Base Sequence, Cell Line, Child, Coxsackievirus Infections, Genetic Vectors, Heart, Hemodynamics, Humans, Molecular Sequence Data, Cardiomyopathies, Myocardium, RNA-Dependent RNA Polymerase, RNA, Viral, Viral Proteins, Enterovirus B, Human, RNA Interference, Mice, Rats
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