Plasmid electrotransfer of eye ciliary muscle: principles and therapeutic efficacy using hTNF-alpha soluble receptor in uveitis.
Due to its small size and particular isolating barriers, the eye is an ideal target for local therapy. Recombinant protein ocular delivery requires invasive and painful repeated injections. Alternatively, a transfected tissue might be used as a local producer of transgene-encoded therapeutic protein. We have developed a nondamaging electrically mediated plasmid delivery technique (electrotransfer) targeted to the ciliary muscle, which is used as a reservoir tissue for the long-lasting expression and secretion of therapeutic proteins. High and long-lasting reporter gene expression was observed, which was restricted to the ciliary muscle. Chimeric TNF-alpha soluble receptor (hTNFR-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 hTNFR-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.
Bloquel
C
C
INSERM, U640, CNRS, UMR8151, René Descartes Paris 5 University, Faculté des Sciences Pharmaceutiques et Biologiques, Chemical and Genetic Pharmacology Laboratory, Ecole Nationale Supérieure de Chimie de Paris, Paris, France.
Bejjani
R
R
Bigey
P
P
Bedioui
F
F
Doat
M
M
BenEzra
D
D
Scherman
D
D
Behar-Cohen
F
F
D000818:Animals; D002924:Ciliary Body / Q000378:metabolism*; D018274:Electroporation / Q000379:methods*; D005260:Female; D015870:Gene Expression; D015316:Genetic Therapy; D006801:Humans; D018482:Muscle, Skeletal; D010957:Plasmids / Q000235:genetics*; D051381:Rats; D011917:Rats, Inbred Lew; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics* / Q000378:metabolism*; D011994:Recombinant Proteins; D012995:Solubility; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D014605:Uveitis / Q000235:genetics* / Q000628:therapy*
D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha