Is P2X7 a potential therapeutic target in the treatment of retinal diseases: an animal study

Abstract

BackgroundAge-related macular degeneration and diabetic retinopathy are the two commonest causes of blindness in the UK and can be regarded as inflammatory diseases of ageing. The P2X7 receptor is thought to play a part in the development of such autoinflammatory conditions, and might be a potential therapeutic target, but its role in ocular inflammation is unknown. The aim of this study was to explore a mouse model of ocular inflammation. MethodsExperimental autoimmune uveitis (EAU) was induced in P2X7–/– and wild-type (WT) mice to test whether P2X7 deficiency could prevent disease induction. Established EAU in B10rIII mice was treated with the P2X7 receptor antagonist A439079 or vehicle to see whether P2X7 blockade was effective in treating disease. Disease activity was observed with endoscopic retinal imaging until animals were culled at day 16. FindingsP2X7 deficiency protected against the development of EAU, with mean disease scores significantly lower in P2X7–/– mice than in control WT mice (n=8, 12 [SD 4] vs n=9, 18 [4]; p=0·03). A439079 also effectively treated established EAU with disease scores in A439079-treated animals significantly lower than in vehicle-treated animals (n=12, 17 [11] vs n=10, 29 [10]; p=0·01). InterpretationOur findings show that P2X7 deficiency can protect against the development of a model of intraocular inflammation in mice and, importantly, that P2X7 antagonists can ameliorate established disease. The P2X7 receptor could be a viable therapeutic target for retinal diseases with an inflammatory pathogenesis; therefore, further studies in other disease models are justified. FundingBiotechnology and Biological Sciences Research Council, GlaxoSmithKline, Novartis.