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Tytuł pozycji:

Effects of ciliary muscle plasmid electrotransfer of TNF-alpha soluble receptor variants in experimental uveitis.

Tytuł :
Effects of ciliary muscle plasmid electrotransfer of TNF-alpha soluble receptor variants in experimental uveitis.
Autorzy :
Touchard E; INSERM, U872 Physiopathology of Ocular Diseases: Therapeutic Innovations, 15 rue de l'Ecole de Médecine, Paris, France.
Bloquel C
Bigey P
Kowalczuk L
Jonet L
Thillaye-Goldenberg B
Naud MC
Scherman D
de Kozak Y
Benezra D
Behar-Cohen F
Pokaż więcej
Źródło :
Gene therapy [Gene Ther] 2009 Jul; Vol. 16 (7), pp. 862-73. Date of Electronic Publication: 2009 May 14.
Typ publikacji :
Journal Article; Research Support, Non-U.S. Gov't
Język :
English
Imprint Name(s) :
Publication: London : Nature Publishing Group
Original Publication: Houndmills, Basingstoke, Hampshire, UK : Macmillan Press Ltd., c1994-
MeSH Terms :
Ciliary Body/*metabolism
Genetic Therapy/*methods
Muscle, Smooth/*metabolism
Receptors, Tumor Necrosis Factor, Type I/*biosynthesis
Recombinant Fusion Proteins/*biosynthesis
Tumor Necrosis Factor Decoy Receptors/*biosynthesis
Uveitis/*therapy
Animals ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Electroporation/methods ; Endotoxins/adverse effects ; Eye/metabolism ; Female ; Gene Transfer Techniques ; Genes, Reporter ; Humans ; Immunomodulation ; Interleukin-10/metabolism ; Interleukin-6/metabolism ; Lac Operon/genetics ; Leukocyte Rolling ; Microscopy, Confocal ; Nitric Oxide Synthase Type II/metabolism ; Plasmids ; Rats ; Rats, Inbred Lew ; Receptors, Tumor Necrosis Factor, Type I/metabolism ; Recombinant Fusion Proteins/metabolism ; Recombinant Fusion Proteins/pharmacology ; Reverse Transcriptase Polymerase Chain Reaction ; Transfection/methods ; Tumor Necrosis Factor Decoy Receptors/metabolism ; Tumor Necrosis Factor-alpha/adverse effects ; Tumor Necrosis Factor-alpha/antagonists & inhibitors ; Tumor Necrosis Factor-alpha/metabolism
Substance Nomenclature :
0 (Endotoxins)
0 (Interleukin-6)
0 (Receptors, Tumor Necrosis Factor, Type I)
0 (Recombinant Fusion Proteins)
0 (Tumor Necrosis Factor Decoy Receptors)
0 (Tumor Necrosis Factor-alpha)
130068-27-8 (Interleukin-10)
1IEO802L3J (recombinant human tumor necrosis factor-binding protein-1)
EC 1.14.13.39 (Nitric Oxide Synthase Type II)
Entry Date(s) :
Date Created: 20090515 Date Completed: 20100730 Latest Revision: 20161125
Update Code :
20220301
DOI :
10.1038/gt.2009.43
PMID :
19440225
Czasopismo naukowe
Intraocular inflammation has been recognized as a major factor leading to blindness. Because tumor necrosis factor-alpha (TNF-alpha) 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-alpha 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-alpha 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-alpha soluble receptors induces a local immunomodulation enabling the control of intraocular inflammation.
Erratum in: Gene Ther. 2009 Aug;16(8):1058. Kowalczuc, L [corrected to Kowalczuk, L].

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