El Zaoui Ikram, Touchard Elodie, Berdugo Marianne, Abadie Claire, Kowalczuk Laura, Deloche Catherine, Zhao Min, Naud Marie-Christine, Combette Jean-Marc, Behar-Cohen Francine
1 INSERM UMRS 1138, Team 17 from Physiopathology of Retinal Diseases to Clinical Developments , Paris, France .
J Ocul Pharmacol Ther. 2015 Feb;31(1):17-24. doi: 10.1089/jop.2014.0019.
XG-102, a TAT-coupled dextrogyre peptide inhibiting the c-Jun N-terminal kinase, was shown efficient in the treatment of experimental uveitis. Preclinical studies are now performed to determine optimal XG-102 dose and route of administration in endotoxin-induced uveitis (EIU) in rats with the purpose of clinical study design.
EIU was induced in Lewis rats by lipopolysaccharides (LPS) injection. XG-102 was administered at the time of LPS challenge by intravenous (IV; 3.2, 35 or 355 μg/injection), intravitreal (IVT; 0.08, 0.2 or 2.2 μg/eye), or subconjunctival (SCJ; 0.2, 1.8 or 22 μg/eye) routes. Controls received either the vehicle (saline) or dexamethasone phosphate injections. Efficacy was assessed by clinical scoring, infiltrating cells count, and expression of inflammatory mediators [inducible nitric oxide synthase (iNOS), cytokine-induced neutrophil chemoattractant-1 (CINC-1)]. The effect of XG-102 on phosphorylation of c-Jun was evaluated by Western blot.
XG-102 demonstrated a dose-dependent anti-inflammatory effect in EIU after IV and SCJ administrations. Respective doses of 35 and 1.8 μg were efficient as compared with the vehicle-injected controls, but only the highest doses, respectively 355 and 22 μg, were as efficient as dexamethasone phosphate. After IVT injections, the anti-inflammatory effect of XG-102 was clinically evaluated similar to the corticoid's effect with all the tested doses. Regardless of the administration route, the lowest efficient doses of XG-102 significantly decreased the ration of phospho c-Jun/total c-Jun, reduced cells infiltration in the treated eyes, and significantly downregulated iNOS and CINC-1 expression in the retina.
These results confirm that XG-102 peptide has potential for treating intraocular inflammation. SCJ injection appears as a good compromise to provide a therapeutic effect while limiting side effects.
XG - 102是一种与TAT偶联的右旋肽，可抑制c - Jun氨基末端激酶，已证明其在治疗实验性葡萄膜炎方面有效。目前正在进行临床前研究，以确定XG - 102在大鼠内毒素诱导性葡萄膜炎（EIU）中的最佳剂量和给药途径，为临床研究设计提供依据。
通过注射脂多糖（LPS）在Lewis大鼠中诱导EIU。在LPS攻击时，通过静脉注射（IV；3.2、35或355μg/注射）、玻璃体内注射（IVT；0.08、0.2或2.2μg/眼）或结膜下注射（SCJ；0.2、1.8或22μg/眼）途径给予XG - 102。对照组接受溶剂（生理盐水）或磷酸地塞米松注射。通过临床评分、浸润细胞计数和炎症介质[诱导型一氧化氮合酶（iNOS）、细胞因子诱导的中性粒细胞趋化因子-1（CINC - 1）]的表达评估疗效。通过蛋白质印迹法评估XG - 102对c - Jun磷酸化的影响。
XG - 102在静脉注射和结膜下注射后对EIU表现出剂量依赖性抗炎作用。与注射溶剂的对照组相比，35μg和1.8μg的相应剂量有效，但只有最高剂量，分别为355μg和22μg，与磷酸地塞米松一样有效。玻璃体内注射后，所有测试剂量的XG - 102的抗炎作用在临床评估中与皮质类固醇的作用相似。无论给药途径如何，XG - 102的最低有效剂量均显著降低磷酸化c - Jun/总c - Jun的比例，减少治疗眼的细胞浸润，并显著下调视网膜中iNOS和CINC - 1的表达。
这些结果证实XG - 102肽具有治疗眼内炎症的潜力。结膜下注射似乎是在提供治疗效果的同时限制副作用的良好折衷方案。
