Hypoxia-regulated retinal glial cell-specific promoter for potential gene therapy in disease
Open accessAbstract
PURPOSE: Retinal Müller cells span the retina and secrete several trophic factors and represent the functional link between blood vessels and neurons, making them attractive targets for gene therapy. Therefore, a hypoxia-regulated, retinal glial cell-specific vector was constructed and tested for its response to hypoxia. METHODS: A hybrid promoter containing domains of human glial fibrillary acidic protein (GFAP) and several hypoxia-responsive and aerobically silenced elements (HRSE) was incorporated separately into plasmid vectors for generation of self-complementary adeno-associated virus. Müller cells trasfected with plasmids or virus were compared with other cell lines using standard METHODS: The mouse model of oxygen-induced retinopathy (OIR) was used to analyze retinas from mice exposed to high oxygen or room air to evaluate the induction of the regulated promoter. RESULTS: The regulated promoter was silenced under aerobic conditions in comparison with unregulated promoter in Müller cells. Hypoxia induced a 12-fold and 16-fold increase in promoter activity in primary Müller cells and human Müller cell lines, respectively. In the OIR model, intravitreal injection of the regulated promoter at postnatal day 7 (P7) resulted in high levels of green fluorescent protein expression only in retinal Müller cells at P17. GFP expression was absent in retinas of mice only exposed to room air. In vivo studies confirm normoxia silencing, hypoxic induction, and cell specificity of the regulated promoter in the mouse retina. CONCLUSIONS: This hypoxia-regulated, retinal glial cell-specific AAV vector provides a platform for gene therapy within regions of retinal hypoxia which are found in diabetic retinopathy and age-related macular degeneration.
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A shortened version of the GFAP promoter called gfaABC1D (686 bp) showed similar expression strength in neurons (brain), whereas the gfaABC1D promoter maintained Müller glial cell-specific expression in the retina.
“Furthermore, a shortened version of the GFAP promoter called gfaABC1D (686 bp) showed similar expression strength in neurons (brain), whereas the gfaABC1D promoter maintained Müller glial cell-specific expression in the retina [96,97].”
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 [97]
The paper describes gfaABC1D as astrocyte-specific in the brain, not as showing expression in neurons; the section on the ABC1D promoter also identifies a segment required to silence neuronal expression. It supports Müller-cell-specific expression in the retina. Figure 1 labels the shortened promoter 686 bp, although the Methods call it 681 bp. (LLM, conf=0.88)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredThe hypoxia-induced Müller glial specific promoter showed no luciferase expression in HEK293, C6, HT22, and ARPE19 cells.
“The hypoxia-induced Müller glial specific promoter showed no luciferase expression in HEK293, C6, HT22, and ARPE19 cells [97].”
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 [97]
The Figure 4 caption says the regulated promoter had basal or minimal expression in HEK, C6, HT22, and ARPE-19 cells, not no expression. The Hypoxic Induction and Cell Specificity section reports no hypoxic induction in those lines; that does not establish an absence of luciferase expression. (LLM, conf=0.88)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredStress (GFAP promoter) or hypoxia-driven GFAP promoters (HRSE-6xHRE-GfaABC1D) have been generated that might be safer for cells that are sensitive to continuous overexpressed artificial gene vectors.
“Stress (GFAP promoter) or hypoxia-driven GFAP promoters (HRSE-6xHRE-GfaABC1D) have been generated that might be safer for cells that are sensitive to continuous overexpressed artificial gene vectors [96,97,99,100,102].”
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 [97]
The Construction section describes the HRSE–6×HRE–GfaABC1D regulated GFAP promoter, and the Results show reduced activity under normal oxygen conditions and induction under hypoxia. The Discussion explains why restricting transgene expression could avoid harm from inappropriate expression, but the paper does not establish that this promoter is safer in cells sensitive to continuous overexpression. (LLM, conf=0.82)
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- Authors
- Prentice, H. M., Biswal, M. R., Dorey, C. K., & Blanks, J. C.
- Affiliations
- From the Center for Complex Systems and Brain Sciences, Charles E. Schmidt College of Science, 2Charles E. Schmidt College of Medicine, and
- Florida Atlantic University (US)
- Virginia Tech (US)
- From the Center for Complex Systems and Brain Sciences, Charles E. Schmidt College of Science,
- Corresponding author
- Prentice, Howard M.
- Biswal, Manas R
- Dorey, C. Kathleen
- Blanks, Janet C.
- Venue
- Investigative Opthalmology & Visual Science
- Published
- 2011-11-01
- Volume
- 52
- Issue
- 12
- Pages
- 8562
- ISSN
- 0146-0404 (ISSN-L)
- 1552-5783
- PMC
- PMC3208385
- OpenAlex
- W1977120970
- Cited by
- 35
- References
- 69
- Citations by year
- 2025: 2 · 2024: 1 · 2023: 2 · 2022: 2 · 2021: 4 · 2020: 4 · 2019: 2 · 2018: 1 · 2017: 3 · 2016: 4 · 2015: 3 · 2014: 5 · 2012: 2
- FWCI
- 0.91
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Investigative Ophthalmology & Visual Science (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Heart Association (0815022E)
- Florida Atlantic University
- Universidad del Atlántico
- National Institutes of Health
- U.S. Public Health Service (EYO16119)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Keywords
- Müller cells, gene therapy vectors, adeno-associated virus vectors, glial fibrillary acidic protein, hypoxia response element, oxygen-induced retinopathy, retinal hypoxia, diabetic retinopathy, age-related macular degeneration, intravitreal gene delivery, cell type-specific gene expression
- MeSH terms
- Adenoviridae, Animals, Hypoxia, Cells, Cultured, Epithelial Cells, Genetic Vectors, Glial Fibrillary Acidic Protein, Humans, Neuroglia, Oxygen, Plasmids, Promoter Regions, Genetic, Retina, Retinal Diseases, Genetic Therapy, Gene Silencing, Mice, HEK293 Cells
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