MPS VI associated ocular phenotypes in an MPS VI murine model and the therapeutic effects of odiparcil treatment.

Maroteaux - Lamy syndrome (mucopolysaccharidosis type VI, MPS VI) is a lysosomal storage disease resulting from insufficient enzymatic activity for degradation of the specific glycosaminoglycans (GAG) chondroitin sulphate (CS) and dermatan sulphate (DS). Among the most pronounced MPS VI clinical manifestations caused by cellular accumulation of excess CS and DS are eye disorders, in particular those that affect the cornea. Ocular manifestations are not treated by the current standard of care, enzyme replacement therapy (ERT), leaving patients with a significant unmet need. Using in vitro and in vivo models, we previously demonstrated the potential of the ß-D-xyloside, odiparcil, as an oral GAG clearance therapy for MPS VI. Here, we characterized the eye phenotypes in MPS VI arylsulfatase B deficient mice (Arsb-) and studied the effects of odiparcil treatment in early and established disease models. Severe levels of opacification and GAG accumulation were detected in the eyes of MPS VI Arsb- mice. Histological examination of MPS VI Arsb- eyes showed an aggregate of corneal phenotypes, including reduction in the corneal epithelium thickness and number of epithelial cell layers, and morphological malformations in the stroma. In addition, colloidal iron staining showed specifically GAG accumulation in the cornea. Orally administered odiparcil markedly reduced GAG accumulation in the eyes of MPS VI Arsb- mice in both disease models and restored the corneal morphology (epithelial layers and stromal structure). In the early disease model of MPS VI, odiparcil partially reduced corneal opacity area, but did not affect opacity area in the established model. Analysis of GAG types accumulating in the MPS VI Arsb- eyes demonstrated major contribution of DS and CS, with some increase in heparan sulphate (HS) as well and all were reduced with odiparcil treatment. Taken together, we further reveal the potential of odiparcil to be an effective therapy for eye phenotypes associated with MPS VI disease.

Comparison of Two Experimental Mouse Dry Eye Models through Inflammatory Gene Set Enrichment Analysis Based on a Multiplexed Transcriptomic Approach.

The goal of this study was to explore the specific signaling pathways related to inflammation in two experimental mouse dry eye (EDE) models. Female C57BL/6 mice housed for 10 days in a controlled desiccative environment were either treated with scopolamine (EDE-1; n = 18) or subjected to extraorbital lacrimal gland excision bilaterally (EDE-2; n = 10). Non-induced mice (n = 20) served as healthy controls. A corneal fluorescein staining (CFS) scoring was used at baseline through to day (D) 10 to evaluate epitheliopathy. At D10, corneas and conjunctivas were collected for multiplexed transcriptomic analysis with the NanoString® mouse inflammatory CodeSet. Both EDE-1 and EDE-2 mice presented a change in corneal integrity, with a significant increase in CFS scores at D10. More gene transcripts were identified in EDE-2 compared with EDE-1 (116 vs. 96, respectively), and only a few were common to both models, 13 for the cornea and 6 for the conjunctiva. The gene functional annotation analysis revealed that the same inflammatory pathways were involved in both models. Comparative profiling of gene expression in the two EDE models leads to the identification of various targets and signaling pathways, which can be extrapolated to and confirmed in human disease.

Efficacy of a new topical cationic emulsion of cyclosporine A on dry eye clinical signs in an experimental mouse model of dry eye.

Dry eye disease (DED) is a complex, multifactorial pathology characterized by corneal epithelium lesions and inflammation. The aim of the present study was to evaluate the efficacy of a cationic emulsion of cyclosporine A (CsA) in a mouse model that mimics severe dry eye. Eight to 12-week-old female C57BL/6N mice with tail patches of scopolamine were housed in controlled environment chambers to induce dry eye. At day three, following dry eye confirmation by corneal fluorescein staining (CFS, score 0-15) and phenol red thread (PRT) lacrimation test, the mice (n = 10/gp) were either treated 3 times a day in both eyes with drug-free cationic emulsion, a 0.1% CsA cationic emulsion, or 1% methylprednisolone (positive control), or non-treated. Aqueous tear production and CFS scores were evaluated at baseline and throughout the treatment period. The lacrimation test confirmed the scopolamine-induced decrease in aqueous production by the lacrimal gland. A reduction of 59% in induced-CFS was observed following topical treatment with 0.1% CsA. The beneficial effect of the cationic emulsion vehicle itself on keratitis was also clearly evidenced by its better performance over 1% methylprednisolone, -36%, vs. -28% on the CFS scores, respectively. This study indicates that the cationic emulsion of CsA (0.1%) was a very effective formulation for the management of corneal epithelium lesions in a severe DED mouse model. In addition, it performed better than a potent glucocorticosteroid (1% methylprednisolone). This cationic emulsion of CsA (0.1%), combining CsA and a tear film oriented therapy (TFOT), i.e. with vehicle properties that mechanically stabilize the tear film, represents a promising new treatment strategy for the management of the signs of dry eye.

The effect of preservatives and antiglaucoma treatments on the ocular surface of mice with dry eye.

PURPOSE: To test the hypothesis that benzalkonium chloride (BAK) alters the ocular surface in normal and dry eye mice and that a BAK-free commercially available antiglaucoma treatment does not induce the same effects. METHODS: Eight- to 12-week-old female C57BL/6 mice were used under normal environmental conditions and in a controlled environment chamber (CEC) which induces dry eye. Study and control groups included treatment with BAK, bimatoprost, BAK-free travoprost, and 0.9% NaCl and nontreated mice exposed and nonexposed to the CEC, respectively. Treatments were instilled 4 times a day in the right eye for 7 days. Aqueous tear production was measured by cotton thread test, corneal fluorescein staining (score 0-15), corneal thickness, goblet cell density, and CD45(+) cell expression in superior, inferior, and fornix conjunctiva by a masked observer. RESULTS: After 7 days of treatment with BAK, mice showed significant increase of corneal staining, reduction of goblet cells, and increase of inflammation under normal and CEC conditions. The commercial preparations of bimatoprost containing BAK and travopost did not show the same effects. Travoprost showed a significant corneal thickening under CEC conditions compared to that in all other groups. CONCLUSIONS: This study indicated that use of BAK has negative effects on the ocular surface under normal and dry eye conditions, even if the association with bimatoprost does not confirm the same results. A BAK-free travoprost preparation showed positive effects on tear secretion and corneal protection.