Trans-Ocular Electric Current In Vivo Enhances AAV-Mediated Retinal Transduction in Large Animal Eye After Intravitreal Vector Administration
Open accessAbstract
Purpose: Electric micro-current has been shown to enhance penetration and transduction of adeno-associated viral (AAV) vectors in mouse retina after intravitreal administration. We termed this: "electric-current vector mobility (ECVM)." The present study considered whether ECVM could augment retinal transduction efficiency of intravitreal AAV8-CMV-EGFP in normal rabbit and nonhuman primate (NHP) macaque. Potential mechanisms underlying enhanced retinal transduction by ECVM were also studied. Methods: We applied an electric micro-current across the intact eye of normal rabbit and monkey in vivo for a brief period immediately after intravitreal injection of AAV8-CMV-EGFP. Retinal GFP expression was evaluated by fundus imaging in vivo. Retinal immunohistochemistry was performed to assess the distribution of retinal cells transduced by the AAV8-EGFP. Basic fibroblast growth factor (bFGF) was analyzed by quantitative RT-polymerase chain reaction (PCR). Müller glial reactivity and inner limiting membrane (ILM) were examined by the glial fibrillary acidic protein (GFAP) and vimentin staining in mouse retina, respectively. Results: ECVM significantly increased the efficiency of AAV reaching and transducing the rabbit retina following intravitreal injection, with gene expression in inner nuclear layer, ganglion cells, and Müller cells. Similar trend of improvement was observed in the ECVM-treated monkey eye. The electric micro-current upregulated bFGF expression in Müller cells and vimentin showed ILM structural changes in mouse retina. Conclusions: ECVM promotes the transduction efficiency of AAV8-CMV-GFP in normal rabbit and monkey retinas following intravitreal injection. Translational Relevance: This work has potential translational relevance to human ocular gene therapy by increasing retinal expression of therapeutic vectors given by intravitreal administration.
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Attempts to manipulate the ILM to reduce the necessary viral load for effective transduction have not resulted in gene expression in the outer retina.
“There have been attempts to manipulate the ILM to reduce the necessary viral load for effective transduction, including the use of proteases to digest the ILM [244,248,249], electric micro-currents [250], and non-penetrating AAV vectors to saturate heparan binding sites in the vitreous [251]. However, these techniques have not resulted in gene expression in the outer retina.”
From Bruch’s Membrane: A Key Consideration with Complement-Based Therapies for Age-Related Macular Degeneration (2023) · cites this paper as [250]
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Hammadi, S., Tzoumas, N., Ferrara, M., Meschede, I. P., Lo, K., Harris, C., Lako, M., & Steel, D. H. (2023) · Journal of Clinical Medicine · doi:10.3390/jcm12082870 · Cited by 44 · see citing works
- Authors
- Song, H., Zeng, Y., Sardar Pasha, S. P. B., Bush, R. A., Vijayasarathy, C., Qian, H., Wei, L., Wiley, H. E., Wu, Z., & Sieving, P. A.
- Affiliations
- National Institutes of Health (US)
- Department of Ophthalmology, School of Medicine, University of California at Davis, Sacramento, CA, USA
- Corresponding author
- Sieving, Paul A.
- Venue
- Translational Vision Science & Technology
- Published
- 2020-06-24
- Volume
- 9
- Issue
- 7
- Pages
- 28
- ISSN
- 2164-2591 (ISSN-L)
- PMC
- PMC7416894
- OpenAlex
- W3037165680
- Cited by
- 9
- References
- 38
- Citations by year
- 2026: 2 · 2025: 3 · 2023: 2 · 2021: 2
- FWCI
- 0.32
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Translational Vision Science & Technology (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- retinal transduction, adeno-associated virus vectors, AAV8, intravitreal injection, ocular gene therapy, basic fibroblast growth factor, Müller cells, internal limiting membrane, retinal ganglion cells, rabbit retina
- MeSH terms
- Dependovirus, Animals, Genetic Vectors, Rabbits, Retina, Transduction, Genetic, Gene Expression
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