A peptide inhibitor of c-Jun N-terminal kinase for the treatment of endotoxin-induced uveitis.
OBJECTIVE
To evaluate the effect of XG-102 (formerly D-JNKI1), a TAT-coupled dextrogyre peptide that selectively inhibits the c-Jun N-terminal kinase, in the treatment of endotoxin-induced uveitis (EIU).


METHODS
EIU was induced in Lewis rats by LPS injection. XG-102 was administered at the time of LPS challenge. The ocular biodistribution of XG-102 was evaluated using immunodetection at 24 hours after either 20 microg/kg IV (IV) or 0.2 microg/injection intravitreous (IVT) administrations in healthy or uveitic eyes. The effect of XG-102 on EIU was evaluated using clinical scoring, infiltration cell quantification, inducible nitric oxide synthase (iNOS) expression and immunohistochemistry, and cytokines and chemokines kinetics at 6, 24, and 48 hours using multiplex analysis on ocular media. Control EIU eyes received vehicle injection IV or IVT. The effect of XG-102 on c-Jun phosphorylation in EIU was evaluated by Western blot in eye tissues.


RESULTS
After IVT injection, XG-102 was internalized in epithelial cells from iris/ciliary body and retina and in glial and microglial cells in both healthy and uveitic eyes. After IV injection, XG-102 was concentrated primarily in inflammatory cells of uveitic eyes. Using both routes of administration, XG-102 significantly inhibited clinical signs of EIU, intraocular cell infiltration, and iNOS expression together with reduced phosphorylation of c-Jun. The anti-inflammatory effect of XG-102 was mediated by iNOS, IFN-gamma, IL-2, and IL-13.


CONCLUSIONS
This is the first evidence that interfering with the JNK pathway can reduce intraocular inflammation. Local administration of XG-102, a clinically evaluated peptide, may have potential for treating uveitis.
Touchard
Elodie
E
INSERM, U872 Physiopathology of Ocular Diseases/Therapeutic Innovations, Paris, France.
Omri
Samy
S
Naud
Marie-Christine
MC
Berdugo
Marianne
M
Deloche
Catherine
C
Abadie
Claire
C
Jonet
Laurent
L
Jeanny
Jean-Claude
JC
Crisanti
Patricia
P
de Kozak
Yvonne
Y
Combette
Jean-Marc
JM
Behar-Cohen
Francine
F
D000818:Animals; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D004338:Drug Combinations; D005260:Female; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / Q000187:drug effects; D056965:Injections, Intraocular; D007275:Injections, Intravenous; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D009821:Oils; D010455:Peptides / Q000493:pharmacokinetics / Q000494:pharmacology*; D010636:Phenols; D051381:Rats; D011917:Rats, Inbred Lew; D015398:Signal Transduction / Q000187:drug effects*; D014018:Tissue Distribution; D014605:Uveitis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D014822:Vitreous Body
D018925:Chemokines; D016207:Cytokines; D004338:Drug Combinations; D008070:Lipopolysaccharides; D009821:Oils; C027222:P & S Liquid; D010455:Peptides; D010636:Phenols; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating); D048031:JNK Mitogen-Activated Protein Kinases; C478085:D-JNKI-1