AAV6 vectors provide superior gene transfer compared to AAV9 vectors following intramyocardial administration
Cardiac gene therapy using adeno-associated viral (AAV) vectors holds great promise for treating heart diseases but would benefit from more potent AAV vectors. Vectors based on the AAV serotypes 6 and 9 have been used in pre-clinical gene therapy studies, yet the therapeutic outcomes varied depending on the experimental model and delivery route used. Here, we evaluated the transduction efficiency of AAV6, AAV9, and AAV9-derived MyoAAVs for local cardiac delivery. Vectors were tested in neonatal rat ventricular myocytes, and subsequently in mouse hearts by direct intramyocardial injection. Vector genome levels, mRNA expression levels, and fluorescence were measured. The AAV6 and AAV9 vectors were further validated in porcine hearts, human-induced pluripotent stem-cell-derived cardiomyocytes, and human atrial myocardial slices. In both rat cardiomyocytes and mouse hearts, AAV6 exhibited the highest transduction efficiency. Direct comparison of the AAV6 and AAV9 vectors in porcine and human models confirmed that AAV6 is more potent. In conclusion, AAV6 vectors are superior to AAV9 and its derivative vectors for cardiac transduction by direct intramyocardial injection. In addition, the <i>in vivo</i> transduction efficiency correlates with <i>in vitro</i> and <i>ex vivo</i> assays, thereby facilitating the development of more potent AAV variants for cardio-selective delivery methods.
Authors
- Joost P. G. Sluijter (ORCID: https://orcid.org/0000-0003-2088-9102)
- Arnie Boender (ORCID: https://orcid.org/0009-0003-3709-9729)
- Gerard J.J. Boink (ORCID: https://orcid.org/0000-0002-6592-5106)
- Timo Jonker (ORCID: https://orcid.org/0000-0001-8713-4156)
- Aina Cervera-Barea (ORCID: https://orcid.org/0000-0003-3944-9756)
- Antoine A.F. de Vries (ORCID: https://orcid.org/0000-0002-4787-7155)
- Vincent M. Christoffels (ORCID: https://orcid.org/0000-0003-4131-2636)
- osne kirzner
- Hanno L. Tan (ORCID: https://orcid.org/0000-0002-7905-5818)
- Klaus Neef (ORCID: https://orcid.org/0000-0001-8271-6552)
- Mischa Klerk (ORCID: https://orcid.org/0000-0002-3725-9943)
- Christian Thirion (ORCID: https://orcid.org/0000-0003-1605-8998)
- Joris R. de Groot (ORCID: https://orcid.org/0000-0002-8122-7017)
- Silke Schrödel (ORCID: https://orcid.org/0000-0002-1520-8299)
- Ya-Chun Yang (ORCID: https://orcid.org/0000-0003-4919-905X)
- Saskia C.A. de Jager (ORCID: https://orcid.org/0000-0002-5233-0066)
- R. Visser (ORCID: https://orcid.org/0000-0003-1775-5461)
- Evelien Birza (ORCID: https://orcid.org/0009-0009-5835-4905)
- Tom C Grootswagers
- Jianan Wang (ORCID: https://orcid.org/0000-0003-1344-237X)
- Zhenyu Dong (ORCID: https://orcid.org/0009-0003-4507-8493)
- Joyce Visser
- Marlijn Jansen
- Cindy I. Bart
Institutions
- Leiden University Medical Center (NL)
- University Medical Center Utrecht (NL)
- Toptica Photonics (Germany) (DE)
- John Benjamins Publishing Company (Netherlands) (NL)
- Netherlands Heart Institute (NL)
- Amsterdam University Medical Centers (NL)
- University of Amsterdam (NL)
- Amsterdam UMC Location Vrije Universiteit Amsterdam (NL)
Publication Details
- Journal
- Molecular Therapy — Methods & Clinical Development
- Published
- 2025-07-16
- DOI
- https://doi.org/10.1016/j.omtm.2025.101532
- Citations
- 3
- Primary Topic
- Virus-based gene therapy research
- Type
- article
- Field-Weighted Citation Impact
- 5.45
Funders
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek
- Horizon 2020 Framework Programme
- Moonshot Research and Development Program
- Eurostars
- HORIZON EUROPE Marie Sklodowska-Curie Actions
- HORIZON EUROPE European Innovation Council