Glial promoter selectivity following AAV-delivery to the immature brain
Open accessAbstract
Recombinant adeno-associated virus (AAV) vectors are versatile tools for gene transfer to the central nervous system (CNS) and proof-of-concept studies in adult rodents have shown that the use of cell type-specific promoters is sufficient to target AAV-mediated transgene expression to glia. However, neurological disorders caused by glial pathology usually have an early onset. Therefore, modelling and treatment of these conditions require expanding the concept of targeted glial transgene expression by promoter selectivity for gene delivery to the immature CNS. Here, we have investigated the AAV-mediated green fluorescent protein (GFP) expression driven by the myelin basic protein (MBP) or glial fibrillary acidic protein (GFAP) promoters in the developing mouse brain. Generally, the extent of transgene expression after infusion at immature stages was widespread and higher than in adults. The GFAP promoter-driven GFP expression was found to be highly specific for astrocytes following vector infusion to the brain of neonates and adults. In contrast, the selectivity of the MBP promoter for oligodendrocytes was poor following neonatal AAV delivery, but excellent after vector injection at postnatal day 10. To extend these findings obtained in naïve mice to a disease model, we performed P10 infusions of AAV-MBP-GFP in aspartoacylase (ASPA)-deficient mouse mutants presenting with early onset oligodendrocyte pathology. Spread of GFP expression and selectivity for oligodendrocytes in ASPA-mutants was comparable with our observations in normal animals. Our data suggest that direct AAV infusion to the developing postnatal brain, utilising cellular promoters, results in targeted and long-term transgene expression in glia. This approach will be relevant for disease modelling and gene therapy for the treatment of glial pathology.
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The mouse Mbp promoter, despite promise, has caveats of murine origin, relatively large size, and poor specificity after neonatal vector delivery.
“While the Mbp promoter holds promise for potential clinical applications, its murine origin, relative big size and poor specificity following neonatal vector delivery, are potential caveats (von Jonquieres et al., 2013).”
From Recombinant Human Myelin-Associated Glycoprotein Promoter Drives Selective AAV-Mediated Transgene Expression in Oligodendrocytes (2016) · cites this paper as von Jonquieres et al., 2013
The Materials and Methods identify the promoter as a 1.94 kb sequence from the mouse mbp gene, and the Discussion reports substantial MBP-promoter leakiness after neonatal delivery. The paper discusses AAV size limits, but does not characterize the MBP promoter’s size or murine origin as clinical caveats; it calls the MBP variants appropriately sized. (LLM, conf=0.84)
Experimental — accuracy not yet measuredTo date, the only cellular promoter used for AAV-mediated transgene expression in oligodendrocytes is the murine 1.9 kb Mbp cis-regulating element and a truncated version spanning the proximal 1.3 kb upstream region including parts of Mbp exon 1.
“To date, the only cellular promoter used for AAV-mediated transgene expression in oligodendrocytes is the murine 1.9 kb Mbp cis-regulating element and a truncated version spanning the proximal 1.3 kb upstream region including parts of Mbp exon 1 (Chen et al., 1998; Lawlor et al., 2009; von Jonquieres et al., 2013).”
From Recombinant Human Myelin-Associated Glycoprotein Promoter Drives Selective AAV-Mediated Transgene Expression in Oligodendrocytes (2016) · cites this paper as von Jonquieres et al., 2013
The Discussion (page unavailable) says there was no appropriately sized, oligodendrocyte-specific alternative to the 1.3 kb and 1.9 kb MBP promoter variants used in AAV studies. Materials and Methods identifies the longer promoter as mouse MBP. Our copy does not establish that the 1.3 kb variant spans the proximal upstream region or includes part of exon 1. (LLM, conf=0.86)
Experimental — accuracy not yet measuredPreclinical proof-of-concept studies in rodents have shown that using cellular promoters can target AAV-mediated transgene expression to glia.
“Preclinical proof-of-concept studies showing successful modification of the AAV system towards selective transgene expression in oligodendrocytes used “neurotropic” serotypes but employed the promoter of the mouse myelin basic protein (Mbp) gene (Chen et al., 1998; Lawlor et al., 2009; von Jonquieres et al., 2013).”
From Recombinant Human Myelin-Associated Glycoprotein Promoter Drives Selective AAV-Mediated Transgene Expression in Oligodendrocytes (2016) · cites this paper as von Jonquieres et al., 2013
In neonates, the MAG promoter might be better suited for transgene expression targeted to oligodendrocytes (90%) than the Mbp promoter (25%).
“Although a comparison between the transduction profiles of the vectors carrying the MAG promoter (this study) and the Mbp promoter (von Jonquieres et al., 2013) is not feasible, it appears that in neonates the MAG promoter might be better suited for transgene expression targeted to oligodendrocytes (90%) than the Mbp promoter (25%).”
From Recombinant Human Myelin-Associated Glycoprotein Promoter Drives Selective AAV-Mediated Transgene Expression in Oligodendrocytes (2016) · cites this paper as von Jonquieres et al., 2013
Vector spread depends on the developmental stage of the target tissue at the time of infusion but not on the cellular promoter used in the expression cassette.
“We have shown previously that the vector spread depends on the developmental stage of the target tissue at the time of infusion but not on the cellular promoter used in the expression cassette (von Jonquieres et al., 2013).”
From Recombinant Human Myelin-Associated Glycoprotein Promoter Drives Selective AAV-Mediated Transgene Expression in Oligodendrocytes (2016) · cites this paper as von Jonquieres et al., 2013
A largely superior vector spread follows neonatal compared with adult AAV delivery to the CNS.
“Moreover, we have previously reported a largely superior vector spread following neonatal compared with adult AAV delivery to the CNS (von Jonquieres et al., 2013).”
From Recombinant Human Myelin-Associated Glycoprotein Promoter Drives Selective AAV-Mediated Transgene Expression in Oligodendrocytes (2016) · cites this paper as von Jonquieres et al., 2013
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Self-citationCanavan Disease as a Model for Gene Therapy-Mediated Myelin Repair
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- Authors
- von Jonquieres, G., Mersmann, N., Klugmann, C. B., Harasta, A. E., Lutz, B., Teahan, O., Housley, G. D., Fröhlich, D., Krämer-Albers, E.-M., & Klugmann, M.
- Affiliations
- Johannes Gutenberg University Mainz (DE)
- UNSW Sydney (AU)
- Corresponding author
- Klugmann, Matthias
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2013-06-14
- Volume
- 8
- Issue
- 6
- Pages
- e65646
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3683058
- OpenAlex
- W2009016214
- Cited by
- 133
- References
- 33
- Citations by year
- 2026: 5 · 2025: 10 · 2024: 6 · 2023: 8 · 2022: 7 · 2021: 14 · 2020: 9 · 2019: 13 · 2018: 11 · 2017: 12 · 2016: 13 · 2015: 9 · 2014: 13 · 2013: 3
- FWCI
- 8.40
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- Association Européenne contre les Leucodystrophies
- 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, myelin basic protein promoter, glial fibrillary acidic protein promoter, astrocytes, oligodendrocytes, neonatal brain development, postnatal brain, aspartoacylase deficiency, lysosomal storage disease, glial pathology, AAV gene therapy, GFP expression
- MeSH terms
- Dependovirus, Age Factors, Animals, Animals, Newborn, Astrocytes, Brain, Cells, Cultured, Myelin Basic Protein, Genetic Vectors, Glial Fibrillary Acidic Protein, Mice, Inbred C57BL, Oligodendroglia, Organ Specificity, Promoter Regions, Genetic, Genetic Therapy, Gene Expression, Canavan Disease, Transgenes, Green Fluorescent Proteins
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