Novel Small Molecule Inhibitors of Ocular Neovascularisation and Optimisation of their Delivery using Microparticles

Abstract

Purpose: Ocular neovascular (ONV) diseases involving the growth of abnormal leaky blood vessels in the eye and retinal oedema are the most common causes of blindness in developed countries. Current treatments involve anti-VEGF therapies; however, a drawback of these drugs is the requirement to attend clinics for regular intraocular injections. We are developing novel small molecule drugs encapsulated within microparticles to provide sustained intraocular efficacy,reducing the risks associated with frequent intraocular injection, decreasing patient, clinical and socioeconomic burden.

Methods: We performed drug screens and validation in zebrafish and mice which identified Quininib ((E)-2-(2-Quinolin-2-yl-vinyl)-phenol HCl salt), a novel small molecule anti-angiogenic drug. Utilising larval zebrafish angiogenesis assays, over forty structural analogues of Quininib are being evaluated. Drug safety and efficacy is currently being tested in mice. Target profiling is determining the mechanism of action of Quininib and Quininib-like compounds. The top ranking drugs have been encapsulated into biodegradable microparticles and are being tested in vitro and in vivo.

Results: Three Quininib-like compounds appear to potently inhibit angiogenesis in the zebrafish eye and their efficacy is being evaluated in mouse ONV models. Target profiling reveals that Quininib and related molecules antagonise the cysteinyl leukotriene and endothelin-converting enzyme pathways. Additionally, we have formulated Quininib into slow release PLGA and alginate microparticles and we are currently evaluating the efficacy and safety of these microparticle formulations in zebrafish. The next goal is to evaluate if sustained release of Quininib and its analogues can be achieved in rodents.

Conclusions: Novel small molecule inhibitors of ocular neovascularisation and inflammation have been identified, with a mechanism of action distinct from current gold-standard VEGF-based drugs. Ultimately, we will examine if our drugs in combination with a novel microparticle device can provide a long term, safe and efficacious therapy in rodent models of ocular neovascularisation, inflammation and retinal oedema, key pathologies associated with age related macular degeneration and diabetic retinopathy. This research may produce a novel, cost-effective, VEGF-independent drug with potential to benefit a wide cohort of patients.

Keywords: 688 retina • 503 drug toxicity/drug effects • 609 neovascularization