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F.F. Behar–Cohen, C. Bloquel, R.A. Bejjani, P. Biggey, F. Bedioui, M. Doat, D. BenEzra, D. Scherman; Electrotransfer Of Plasmids In The Ciliary Muscle: Principle And Potential Therapeutic Application . Invest. Ophthalmol. Vis. Sci. 2006;47(13):5107.
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Our purpose was to develop a non damaging electrically mediated plasmid delivery technique (electrotransfer) targeted to the ciliary muscle, which can be used as a reservoir tissue for the long–lasting expression and secretion of therapeutic proteins. We then assess the potentiality of this technology in an experimental uveitis model.
We designed electrodes and validate electrical conditions suitable for electrotransfer of the ciliary muscle. Localization of the transgene expression was evaluted thanks to GFP reporter gene expression, and kinetic of the expression in the ciliary muscle was evaluated by in vitro measurement of luminescence in ciliary muscle electrotransfered with a luciferase encoding plasmid. Clinical, histological, and TUNEL analysis were performed to ensure the safety of the procedure. EIU was induced in Lewis rats by a single footpad injection of 150 µg Salmonella Typhimurium lipopolysaccharide (LPS). Rats were treated by electrotransfer in the ciliary muscle of a plasmid encoding a chimeric TNF–alpha soluble receptor linked to the Fc fragment of IgG1 (TNFR–Is/IgG1). A single treatment was administred 6 days before the induction of the disease. Twenty–for hours after the disease induction, clinical and histological analyses were performed. Local and systemic TNF–alpha and TNFR–Is rates were also evaluated at this time point.
High and long–lasting reporter gene expression was observed, which was restricted to the ciliary muscle. TNFR–Is electrotransfer led to elevated protein secretion in aqueous humor and to drastic inhibition of clinical and histological inflammation scores in rats with endotoxin–induced uveitis. No TNFR–Is was detected in the serum, demonstrating the local delivery of proteins using this method. Plasmid electrotransfer to the ciliary muscle, as performed in this study, did not induce any ocular pathology or structural damage.
Local and sustained therapeutic protein production through ciliary muscle electrotransfer is a promising alternative to repeated intraocular protein administration for a large number of inflammatory, degenerative, or angiogenic diseases.
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