Narrow spectrum kinase inhibitors demonstrate promise for the treatment of dry eye disease and other ocular inflammatory disorders

Suzanne Hagan, Matthew C.T. Fyfe, Boatemaa Ofori-Frimpong, Katherine Oliver, Martyn R. Foster, Sameer Sirohi, Yemisi Solanke, Michael Doughty, Adele Rowley, Mike Taylor, Steve Webber, Claire A. Walshe*

*Corresponding author for this work

Research output: Contribution to journalArticle

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Abstract

PURPOSE:
The purpose of this study is to determine the potential of narrow spectrum kinase inhibitors (NSKIs) to treat inflammatory eye disorders.

METHODS:
Human conjunctival epithelial (HCE) cells were retrieved from subjects via impression cytology. Real-time quantitative PCR (qPCR) was performed on HCE cells to determine gene expression of NSKI kinase targets and proinflammatory cytokines in dry eye disease (DED) patients versus healthy controls. qPCR also assessed p38a expression in hyperosmolar-treated Chang conjunctival epithelial cells. Interaction of NSKI TOP1362 with the kinases was evaluated in ATP-dependent Z-LYTE and competition binding assays. Anti-inflammatory activity was assessed in human peripheral blood mononuclear cells and primary macrophages. In an endotoxin-induced uveitis (EIU) study, lipopolysaccharide (LPS) was administered intravitreally to Lewis rats. TOP1362, dexamethasone, or vehicle was administered topically, and inflammatory cytokine levels were measured 6 hours after LPS injection.

RESULTS:
HCE cells from DED patients showed significantly increased expression of p38a, spleen tyrosine kinase (Syk), Src, lymphocyte-specific protein tyrosine kinase (Lck), interleukin one beta (IL-1ß), interleukin eight (IL-8), monocyte chemotactic protein-1 (MCP-1), and matrix metalloproteinase-9 (MMP-9). TOP1362 strongly inhibited the kinase targets p38a, Syk, Src, and Lck, blocked the rise in p38a expression in hyperosmolar Chang cells, and potently reduced inflammatory cytokine release in cellular models of innate and adaptive immunities. In the EIU model, TOP1362 dose-dependently attenuated the LPS-induced rise in inflammatory cell infiltration and ocular cytokine levels with efficacy comparable to that of dexamethasone.

CONCLUSIONS:
TOP1362 is a potent inhibitor of kinases upregulated in DED and markedly attenuates proinflammatory cytokine release in vitro and in vivo, highlighting the therapeutic potential of NSKIs for treating ocular inflammation, such as that observed in DED.
Original languageEnglish
Pages (from-to)1443-1453
Number of pages11
JournalInvestigative Ophthalmology and Visual Science
Volume59
Issue number3
DOIs
Publication statusPublished - 31 Mar 2018

Keywords

  • kinase inhibitor
  • dry eye disease
  • endotoxin-induced uveitis
  • inflammation

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    Hagan, S., Fyfe, M. C. T., Ofori-Frimpong, B., Oliver, K., Foster, M. R., Sirohi, S., Solanke, Y., Doughty, M., Rowley, A., Taylor, M., Webber, S., & Walshe, C. A. (2018). Narrow spectrum kinase inhibitors demonstrate promise for the treatment of dry eye disease and other ocular inflammatory disorders. Investigative Ophthalmology and Visual Science, 59(3), 1443-1453. https://doi.org/10.1167/iovs.17-23479