A Peptide Inhibitor of c-Jun N-Terminal Kinase for the Treatment of Endotoxin-Induced Uveitis

作者：Touchard Elodie; Omri Samy; Naud Marie Christine; Berdugo Marianne; Deloche Catherine; Abadie Claire; Jonet Laurent; Jeanny Jean Claude; Crisanti Patricia; de Kozak Yvonne; Combette Jean Marc; Behar Cohen Francine^*

来源：Investigative Ophthalmology & Visual Science, 2010, 51(9): 4683-4693.

DOI：10.1167/iovs.09-4733

PURPOSE. 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 immuno-detection at 24 hours after either 20 mu g/kg IV (IV) or 0.2 mu g/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. (Invest Ophthalmol Vis Sci. 2010; 51: 4683-4693) DOI: 10.1167/iovs.09-4733

• 出版日期2010-9