Dry eye syndrome: The establishment of an optimized animal model and the evaluation of novel treatment options
8 juni 2017
Campus Drie Eiken - Gebouw R - Auditorium R1 - Universiteitsplein 1 - 2610 Antwerpen (Wilrijk)
17 - 19 uur
Doctoraatsverdediging Cedric Joossen - Departement Farmaceutische Wetenschappen
Dry eye syndrome (DES) is a common disorder with a rising prevalence. Dysfunction of the tear film leads to disruption of ocular surface homeostasis and initiates chronic ocular inflammation. Current treatment options are limited and often unsatisfactory.
Many different animal models are described to study the pathogenesis of dry. These models often employ dry eye inducing agents which a) potentially interfere with topical delivery of treatments b) require labour intensive follow up c) have systemic side effects d) don’t mimic the pathogenesis of dry eye. Additionally, most of these models have a limited set of evaluation parameters that can be routinely used for in depth study of the pathogenesis of dry eye. In this work, a surgical animal model for dry has been optimized and validated and relevant immunological parameters have been implemented.
The bioavailability of a pharmacon through conventional topical application of eye drops is low due to corneal barrier function and lacrimation. Ocular inserts and gels present an opportunity to increase the residence time and bioavailability of these drugs. In vivo evaluation of chitosan inserts, loaded with Cyclosporin A, concluded that chitosan-based inserts in its dry, rigid form, are not suitable for tear deficient dry eye. The moisture absorbing properties of the insert coincided with residual tear volume and ocular tolerance.
A HPMC-based aqueous gel was presented as an alternative formulation and loaded with dexamethasone sodium phosphate. This formulation displayed adequate ocular tolerance. However, no significant effect of the inserts on dry eye parameters was registered.
Benzalkonium chloride, a common preservative in ocular products, was shown to aggravate dry eye signs, highlighting the need to exclude this chemical from eye care products.
The broad range trypsin-like serine protease inhibitor UAMC0050 showed an in vivo statistically significant improvement on ocular surface damage. Moreover, treatment with UAMC0050 significantly lowered tear cytokine concentrations and resulted in a significant decrease of CD3+ and CD45+ cell populations in conjunctival tissue. Additionally, an accumulation of pro-MMP-9 and decreased levels of active MMP-9 in tear fluid from UAMC0050 treated rats was observed, compared to untreated and vehicle treated animals. In multiple experiments this inhibitor confirmed its potency and outperformed the positive control cyclosporin A (Restasis®). This, together with the observation of an elevated expression of trypsin-like serine proteases in ocular tissue, suggest an important role of these serine proteases in the pathogenesis of dry eye in the animal model employed in this study.