AAV2-VEGF-B gene therapy failed to induce angiogenesis in ischemic porcine myocardium due to inflammatory responses
Open accessAbstract
Therapeutic angiogenesis induced by gene therapy is a promising approach to treat patients suffering from severe coronary artery disease. In small experimental animals, adeno-associated viruses (AAVs) have shown good transduction efficacy and long-term transgene expression in heart muscle and other tissues. However, it has been difficult to achieve cardiac-specific angiogenic effects with AAV vectors. We tested the hypothesis whether AAV2 gene transfer (1 × 10 13 vg) of vascular endothelial growth factor B (VEGF-B186) together with immunosuppressive corticosteroid treatment can induce long-term cardiac-specific therapeutic effects in the porcine ischemic heart. Gene transfers were delivered percutaneously using direct intramyocardial injections, improving targeting and avoiding direct contact with blood, thus reducing the likelihood of immediate immune reactions. After 1- and 6-month time points, the capillary area was analyzed, myocardial perfusion reserve (MPR) was measured with radiowater positron emission tomography ([15 O]H 2 O-PET), and fluorodeoxyglucose ([18 F]FDG) uptake was used to evaluate myocardial viability. Clinical chemistry and immune responses were analyzed using standard methods. After 1- and 6-month follow-up, AAV2-VEGF-B186 gene transfer failed to induce angiogenesis and improve myocardial perfusion and viability. Here, we show that inflammatory responses attenuated the therapeutic effect of AAV2 gene transfer by significantly reducing successful transduction and long-term gene expression despite the efforts to reduce the likelihood of immune reactions and the use of targeted local gene transfer methods.
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AAV-elicited immune responses can limit efficient gene transduction.
“Despite the advantages and promising results from preclinical and clinical trials, AAVs have been shown to elicit immune responses (MacLachlan et al., 2011; Russell et al., 2017), and these responses can limit efficient gene transduction (Korpela et al., 2022).”
From AAV2 and AAV9 tropism and transgene expression in the mouse eye and major tissues after intravitreal and subretinal delivery (2023) · cites this paper as Korpela et al., 2022
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Koponen, S., Kokki, E., Tamminen, T., & Ylä-Herttuala, S. (2023) · Frontiers in Drug Delivery · doi:10.3389/fddev.2023.1148795 · Cited by 21 · see citing works
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- Authors
- Korpela, H., Lampela, J., Airaksinen, J., Järveläinen, N., Siimes, S., Valli, K., Nieminen, T., Turunen, M., Grönman, M., Saraste, A., Knuuti, J., Hakulinen, M., Poutiainen, P., Kärjä, V., Nurro, J., & Ylä-Herttuala, S.
- Affiliations
- University of Eastern Finland (FI)
- University of Turku (FI)
- Kuopio University Hospital (FI)
- ORCID
- Venue
- Gene Therapy
- Published
- 2022-02-07
- Volume
- 29
- Issue
- 10-11
- Pages
- 643-652
- ISSN
- 0969-7128 (ISSN-L)
- 1476-5462
- PMC
- PMC9684066
- OpenAlex
- W4210518486
- Cited by
- 22
- References
- 36
- Citations by year
- 2026: 6 · 2025: 5 · 2024: 4 · 2023: 5 · 2022: 2
- FWCI
- 2.41
- Type
- journal article
- Language
- en
- Update notices
- correction (2024-08-26)
- Open access
- hybrid
- doi.org
- Locations
- Gene Therapy (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- UTUPub (University of Turku) (submittedVersion, other-oa)
- Funders
- Itä-Suomen Yliopisto
- Kuopion Yliopistollinen Sairaala
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- therapeutic angiogenesis, myocardial ischemia, porcine model, inflammation, corticosteroid immunosuppression, intramyocardial injection, myocardial perfusion reserve, myocardial viability
- MeSH terms
- Dependovirus, Animals, Genetic Vectors, Myocardium, Swine, Genetic Therapy, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factor B
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