Local Ocular Immunomodulation Resulting from Electrotransfer of Plasmid Encoding Soluble TNF Receptors in the Ciliary Muscle
Open accessAbstract
PURPOSE: Plasmid electrotransfer in the ciliary muscle allows the sustained release of therapeutic proteins within the eye. The aim of this study was to evaluate whether the ocular production of TNF-alpha soluble receptor, using this nonviral gene therapy method, could have a beneficial local effect in a model of experimental autoimmune uveoretinitis (EAU). METHODS: Injection of a plasmid encoding a TNF-alpha p55 receptor (30 microg) in the ciliary muscle, combined with electrotransfer (200 V/cm), was carried out in Lewis rat eyes 4 days before the induction of EAU by S-antigen. Control eyes received naked plasmid electrotransfer or simple injection of the therapeutic plasmid. The disease was evaluated clinically and histologically. Cytokines and chemokines were analyzed in the ocular media by multiplex assay performed 15 and 21 days after immunization. RESULTS: Ocular TNF-alpha blockade, resulting from the local secretion of soluble receptors, was associated with delayed and significantly less severe uveitis, together with a reduction of the retinal damages. Compared with the controls, treated eyes showed significantly lower levels of IL-1beta and MCP1, higher levels of IL-13 and IL-4, and reduced NOS-2 expression in infiltrating cells. Treatment did not influence TNF-alpha levels in inguinal lymph nodes. CONCLUSIONS: Taken together, these results indicate that local immunomodulation was achieved and that no systemic adverse effects of TNF-alpha blockade observed after systemic injection of TNF-alpha inhibitors should be expected.
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Postoperative inflammation after electrotransfection could not be accurately assessed because the studies were done on animal models of intraocular inflammation.
“Postoperative inflammation could not be accurately assessed as the studies were done on animal models of intraocular inflammation.”
From Ocular Gene Therapy: A Literature Review with Special Focus on Immune and Inflammatory Responses (2022) · cites this paper as [33]
The Experimental Design and Electrotransfer to Ciliary Muscle section (page not indicated) confirms that the study used electrotransfer in rats before inducing experimental autoimmune uveitis. The paper does not say that postoperative inflammation could not be accurately assessed because of that model; its Induction and Clinical Assessment of EAU section instead describes assessment of uveitis severity. (LLM, conf=0.84)
Experimental — accuracy not yet measuredIn studies performed on rabbits and rodents, there were no reported safety issues with electrotransfection.
“In different studies performed on rabbits and rodents, there were no reported safety issues.33,102–104”
From Ocular Gene Therapy: A Literature Review with Special Focus on Immune and Inflammatory Responses (2022) · cites this paper as [33]
The Experimental Design section describes electrotransfer in rats, and the Discussion reports no circulating soluble receptors in treated rats, suggesting that systemic adverse effects associated with injected TNF inhibitors should not result. The paper does not report rabbit experiments or establish that electrotransfer had no safety issues overall. (LLM, conf=0.78)
Experimental — accuracy not yet measuredElectrotransfection was effective in decreasing ocular inflammation in animal models of intraocular inflammation.
“However, the studies demonstrated that electrotransfection was effective in decreasing ocular inflammation in these models.33,102–104”
From Ocular Gene Therapy: A Literature Review with Special Focus on Immune and Inflammatory Responses (2022) · cites this paper as [33]
There were no histological or functional electroretinogram toxicities following electrotransfection.
“There were no histological or functional (electroretinogram) toxicities following electrotransfection.”
From Ocular Gene Therapy: A Literature Review with Special Focus on Immune and Inflammatory Responses (2022) · cites this paper as [33]
The Photoreceptor Rescue section (page unavailable) reports less histologic damage in treated rats with autoimmune uveoretinitis, but that measures disease severity rather than whether electrotransfer itself caused toxicity. Searches for electroretinogram/ERG and ocular toxicity found no functional safety assessment or statement that histological toxicity was absent. (LLM, conf=0.76)
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- Authors
- Kowalczuk, L., Touchard, E., Camelo, S., Naud, M.-C., Castaneda, B., Brunel, N., Besson-Lescure, B., Thillaye-Goldenberg, B., Bigey, P., BenEzra, D., de Kozak, Y., & Behar-Cohen, F.
- Affiliations
- Inserm (FR)
- From the INSERM UMRS 872 Team17, Centre de Recherches des Cordeliers, Universite´ Pierre et Marie Curie, Universite´ Paris Descartes, Paris, France;
- Centre National de la Recherche Scientifique (FR)
- From the INSERM UMRS 872 Team17, Centre de Recherches des Cordeliers, Universite´ Pierre et Marie Curie, Universite´ Paris Descartes, Paris, France;7Department of Ophthalmology, Ho^tel-Dieu Hospital, Paris, France.
- Venue
- Investigative Opthalmology & Visual Science
- Published
- 2009-04-01
- Volume
- 50
- Issue
- 4
- Pages
- 1761
- ISSN
- 0146-0404 (ISSN-L)
- 1552-5783
- OpenAlex
- W1966264899
- Cited by
- 25
- References
- 43
- Citations by year
- 2024: 1 · 2022: 1 · 2021: 2 · 2020: 2 · 2019: 2 · 2018: 1 · 2017: 1 · 2016: 1 · 2015: 1 · 2013: 1 · 2012: 4
- FWCI
- 4.07
- Type
- journal article
- Language
- en
- Open access
- green
- hal.science
- Licence
- other-oa
- Locations
- Investigative Ophthalmology & Visual Science (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion, other-oa)
- IRIS (submittedVersion)
- SERVAL (Université de Lausanne) (submittedVersion)
- Topics
- Health Sciences › Medicine › Ophthalmology › Ocular Diseases and Behçet’s Syndrome
- Health Sciences › Medicine › Ophthalmology › Ocular Oncology and Treatments
- Health Sciences › Medicine › Ophthalmology › Glaucoma and retinal disorders
- Keywords
- ciliary muscle, soluble TNF-alpha receptor, TNF-alpha blockade, experimental autoimmune uveoretinitis, ocular gene therapy, non-viral gene therapy, local immunomodulation, S-antigen, retinal damage, cytokines, chemokines, IL-13, IL-4, IL-1β, MCP-1, nitric oxide synthase 2, Lewis rats
- MeSH terms
- Animals, Autoimmune Diseases, Ciliary Body, Disease Models, Animal, Male, Muscle, Smooth, Plasmids, Rats, Inbred Lew, Genetic Therapy, Uveitis, Posterior, Gene Expression, Electroporation, Chemokines, Fluorescent Antibody Technique, Indirect, Arrestin, Reverse Transcriptase Polymerase Chain Reaction, Receptors, Tumor Necrosis Factor, Type I, Rats, Nitric Oxide Synthase Type II, Tumor Necrosis Factor Decoy Receptors
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