Narrow spectrum kinase inhibitors (NSKIs) are superior to corticosteroid in both in vitro and in vivo inflammatory eye models

Abstract

Purpose : Inflammatory eye diseases, such as uveitis and dry eye syndrome, can be debilitating and in severe cases lead to visual impairment. Despite recent therapeutic advances, corticosteroids (CS) followed by steroid-sparing immunosuppressants remain the mainstay treatment options. However, long term use of CS is complicated by the development of cataract and glaucoma. NSKIs are a novel class of small molecule which selectively target key kinases (p38-alpha, Src family kinases and Syk) involved in both innate and adaptive inflammatory signalling cascades. Here, we compare an NSKI to CS in in vitro and in vivo inflammatory eye models.

Methods : Efficacy and potency of the NSKI TOP1106 was compared to the CS, fluticasone propionate, using in vitro cell assays representative of innate immunity (lipopolysaccharide (LPS) stimulated peripheral blood mononuclear cells (PBMCs) and primary human macrophages), adaptive immunity (anti-CD3/anti-CD28 stimulated PBMCs) and TNFα/IL-1β stimulated primary human retinal pigment epithelial cells (RPE). In vivo, TOP1106 and dexamethasone were tested in a rat LPS-induced uveitis (EIU) model using cellular infiltrate into the aqueous humor and inflammatory cytokine levels in eye tissue as endpoints to assess efficacy.

Results : TOP1106 exhibited a broader and more potent in vitro anti-inflammatory profile compared to CS. In both innate and adaptive immune responses, TOP1106 is a potent inhibitor (IC₅₀s < 20 nM) of inflammatory cytokine release and was superior to CS both in terms of potency and efficacy. Similarly, in stimulated RPE cells TOP1106 was markedly more potent than CS in inhibiting IL-6, IL-8 and CCL-5 release. In the EIU model, topical administration of TOP1106 (1 mg/ml) was more efficacious than CS (1 mg/ml) in reducing inflammatory cytokines MCP-1, IL-6 and IL-1β in both anterior and posterior tissues of the eye, as well as inflammatory cell infiltrate into the aqueous humor.

Conclusions : This data demonstrates the potential utility of NSKIs in the treatment of ocular inflammation. With the ability to target both innate and adaptive immunity pathways, NSKIs achieve comparable, if not superior, efficacy to CS thereby offering a potential alternative to avoid the complications of long term CS use.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.