Effects of ciliary muscle plasmid electrotransfer of TNF-α soluble receptor variants in experimental uveitis View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2009-05-14

AUTHORS

E Touchard, C Bloquel, P Bigey, L Kowalczuc, L Jonet, B Thillaye-Goldenberg, M-C Naud, D Scherman, Y de Kozak, D BenEzra, F Behar-Cohen

ABSTRACT

Intraocular inflammation has been recognized as a major factor leading to blindness. Because tumor necrosis factor-α (TNF-α) enhances intraocular cytotoxic events, systemic anti-TNF therapies have been introduced in the treatment of severe intraocular inflammation, but frequent re-injections are needed and are associated with severe side effects. We have devised a local intraocular nonviral gene therapy to deliver effective and sustained anti-TNF therapy in inflamed eyes. In this study, we show that transfection of the ciliary muscle by plasmids encoding for three different variants of the p55 TNF-α soluble receptor, using electrotransfer, resulted in sustained intraocular secretion of the encoded proteins, without any detection in the serum. In the eye, even the shorter monomeric variant resulted in efficient neutralization of TNF-α in a rat experimental model of endotoxin-induced uveitis, as long as 3 months after transfection. A subsequent downregulation of interleukin (IL)-6 and iNOS and upregulation of IL-10 expression was observed together with a decreased rolling of inflammatory cells in anterior segment vessels and reduced infiltration within the ocular tissues. Our results indicate that using a nonviral gene therapy strategy, the local self-production of monomeric TNF-α soluble receptors induces a local immunomodulation enabling the control of intraocular inflammation. More... »

PAGES

862-873

Journal

TITLE

Gene Therapy

ISSUE

7

VOLUME

16

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/gt.2009.43

DOI

http://dx.doi.org/10.1038/gt.2009.43

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1008600798

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/19440225


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36 schema:description Intraocular inflammation has been recognized as a major factor leading to blindness. Because tumor necrosis factor-α (TNF-α) enhances intraocular cytotoxic events, systemic anti-TNF therapies have been introduced in the treatment of severe intraocular inflammation, but frequent re-injections are needed and are associated with severe side effects. We have devised a local intraocular nonviral gene therapy to deliver effective and sustained anti-TNF therapy in inflamed eyes. In this study, we show that transfection of the ciliary muscle by plasmids encoding for three different variants of the p55 TNF-α soluble receptor, using electrotransfer, resulted in sustained intraocular secretion of the encoded proteins, without any detection in the serum. In the eye, even the shorter monomeric variant resulted in efficient neutralization of TNF-α in a rat experimental model of endotoxin-induced uveitis, as long as 3 months after transfection. A subsequent downregulation of interleukin (IL)-6 and iNOS and upregulation of IL-10 expression was observed together with a decreased rolling of inflammatory cells in anterior segment vessels and reduced infiltration within the ocular tissues. Our results indicate that using a nonviral gene therapy strategy, the local self-production of monomeric TNF-α soluble receptors induces a local immunomodulation enabling the control of intraocular inflammation.
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44 TNF
45 anti-TNF therapy
46 blindness
47 cells
48 ciliary muscle
49 control
50 cytotoxic events
51 detection
52 different variants
53 downregulation
54 effect
55 efficient neutralization
56 electrotransfer
57 events
58 experimental model
59 experimental uveitis
60 expression
61 eyes
62 factors
63 gene therapy
64 gene therapy strategies
65 iNOS
66 immunomodulation
67 infiltration
68 inflamed eyes
69 inflammation
70 inflammatory cells
71 interleukin
72 intraocular inflammation
73 local immunomodulation
74 major factor
75 model
76 monomeric variant
77 months
78 muscle
79 necrosis factor
80 neutralization
81 nonviral gene therapy
82 nonviral gene therapy strategies
83 ocular tissues
84 p55 TNF
85 plasmid
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87 protein
88 rat experimental model
89 receptor variants
90 receptors
91 reduced infiltration
92 results
93 rolling
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95 segment vessels
96 serum
97 severe intraocular inflammation
98 severe side effects
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100 soluble receptor
101 strategies
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103 subsequent downregulation
104 therapy
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