A synthetic AAV vector enables safe and efficient gene transfer to the mammalian inner ear
Open accessAbstract
Efforts to develop gene therapies for hearing loss have been hampered by the lack of safe, efficient, and clinically relevant delivery modalities. Here we demonstrate the safety and efficiency of Anc80L65, a rationally designed synthetic vector, for transgene delivery to the mouse cochlea. Ex vivo transduction of mouse organotypic explants identified Anc80L65 from a set of other adeno-associated virus (AAV) vectors as a potent vector for the cochlear cell targets. Round window membrane injection resulted in highly efficient transduction of inner and outer hair cells in mice, a substantial improvement over conventional AAV vectors. Anc80L65 round window injection was well tolerated, as indicated by sensory cell function, hearing and vestibular function, and immunologic parameters. The ability of Anc80L65 to target outer hair cells at high rates, a requirement for restoration of complex auditory function, may enable future gene therapies for hearing and balance disorders.
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Later studies characterized Anc80L65, demonstrating great transduction efficiency for retinas, inner ear, and notable expression in the CNS after systemic gene transfer.
“Later, more studies further characterized the vector Anc80L65, demonstrating great transduction efficiency for retinas [71], inner ear [72], and even notable expression in the CNS after systemic gene transfer [73].”
From Designing and optimizing AAV-mediated gene therapy for neurodegenerative diseases: from bench to bedside (2024) · cites this paper as [72]
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- Authors
- Landegger, L. D., Pan, B., Askew, C., Wassmer, S. J., Gluck, S. D., Galvin, A., Taylor, R., Forge, A., Stankovic, K. M., Holt, J. R., & Vandenberghe, L. H.
- Affiliations
- Massachusetts Eye and Ear Infirmary (US)
- Boston Children's Hospital (US)
- University College London (GB)
- Corresponding author
- Holt, Jeffrey R
- Vandenberghe, Luk H
- ORCID
- Venue
- Nature Biotechnology
- Published
- 2017-02-06
- Volume
- 35
- Issue
- 3
- Pages
- 280-284
- ISSN
- 0733-222X (ISSN-L)
- 1087-0156
- 1546-1696
- PMC
- PMC5340646
- OpenAlex
- W2586762515
- Cited by
- 325
- References
- 39
- Citations by year
- 2026: 27 · 2025: 28 · 2024: 30 · 2023: 33 · 2022: 39 · 2021: 34 · 2020: 53 · 2019: 30 · 2018: 31 · 2017: 20
- FWCI
- 23.76
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature Biotechnology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- UCL Discovery (University College London) (submittedVersion)
- UNC Libraries
- Funders
- U.S. Department of Defense (W81XWH-15–1-, W81XWH, W81XWH1510472)
- Fondation Bertarelli
- Grousbeck Family Foundation
- Rosetrees Trust (M58-F1)
- National Institutes of Health (1dp1od008267-01, W81XWH)
- National Eye Institute (DP1EY023177)
- National Institute on Deafness and Other Communication Disorders (R01DC015824)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD090255)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Life Sciences › Neuroscience › Sensory Systems › Hearing, Cochlea, Tinnitus, Genetics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- adeno-associated virus vectors, inner hair cells, outer hair cells, vestibular function, hearing restoration, balance disorders
- MeSH terms
- Dependovirus, Animals, Cochlea, Genetic Vectors, Mice, Inbred C57BL, Plasmids, Transduction, Genetic, Genetic Therapy, Mice
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