Molecular evolution of adeno-associated virus for enhanced glial gene delivery
Open accessAbstract
The natural tropism of most viral vectors, including adeno-associated viral (AAV) vectors, leads to predominant transduction of neurons and epithelia within the central nervous system (CNS) and retina. Despite the clinical relevance of glia for homeostasis in neural tissue, and as causal contributors in genetic disorders such as Alzheimer's and amyotrophic lateral sclerosis, efforts to develop more efficient gene delivery vectors for glia have met with limited success. Recently, viral vector engineering involving high-throughput random diversification and selection has enabled the rapid creation of AAV vectors with valuable new gene delivery properties. We have engineered novel AAV variants capable of efficient glia transduction by employing directed evolution with a panel of four distinct AAV libraries, including a new semi-random peptide replacement strategy. These variants transduced both human and rat astrocytes in vitro up to 15-fold higher than their parent serotypes, and injection into the rat striatum yielded astrocyte transduction levels up to 16% of the total transduced cell population, despite the human astrocyte selection platform. Furthermore, one variant exhibited a substantial shift in tropism toward Müller glia within the retina, further highlighting the general utility of these variants for efficient glia transduction in multiple species within the CNS and retina.
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Subretinal AAV vector injection enables efficient gene expression in several retinal cell types, including photoreceptors and retinal pigment epithelial cells.
“Subretinal AAV vector injection, used for the LCA and choroideremia trials, enables efficient gene expression in several retinal cell types, including photoreceptors and retinal pigment epithelial cells.16,17”
From Antibody neutralization poses a barrier to intravitreal adeno-associated viral vector gene delivery to non-human primates (2015) · cites this paper as [16]
The capsid composition of rAAV can be adjusted to fit one's goals.
“The capsid composition can be adjusted to fit one's goals [25].”
From Recombinant Adeno-Associated Viral Vectors (rAAV)-Vector Elements in Ocular Gene Therapy Clinical Trials and Transgene Expression and Bioactivity Assays (2020) · cites this paper as [25]
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- Authors
- Koerber, J. T., Klimczak, R., Jang, J.-H., Dalkara, D., Flannery, J. G., & Schaffer, D. V.
- Affiliations
- University of California, Berkeley (US)
- Corresponding author
- Schaffer, David V
- Venue
- Molecular Therapy
- Publisher
- Elsevier BV
- Published
- 2009-12
- Volume
- 17
- Issue
- 12
- Pages
- 2088-2095
- ISSN
- 1525-0016 (ISSN-L)
- PMC
- PMC2788045
- OpenAlex
- W2117029319
- Cited by
- 181
- References
- 54
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 14 · 2023: 8 · 2022: 10 · 2021: 11 · 2020: 12 · 2019: 6 · 2018: 5 · 2017: 11 · 2016: 10 · 2015: 18 · 2014: 14 · 2013: 13 · 2012: 10
- FWCI
- 7.21
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular Therapy (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Eye Institute (R21EY016994, R01EY014375)
- National Institute of General Medical Sciences (T32 GM08352, T32GM008352)
- 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
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Keywords
- adeno-associated virus vectors, Müller cells, viral tropism, directed evolution, AAV serotypes, central nervous system, retina, striatum, viral vector engineering
- MeSH terms
- Dependovirus, Animals, Astrocytes, Cells, Cultured, Genetic Vectors, Glioblastoma, Humans, Neuroblastoma, Serotyping, Transduction, Genetic, Drug Delivery Systems, Rats, Sprague-Dawley, Gene Transfer Techniques, Directed Molecular Evolution, Green Fluorescent Proteins, Rats
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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