Ocular surface response of two preservative-free cylcosporine A emulsion eye drops in a mouse model of dry eye

Abstract

Purpose/Aim: Dry eye (DE) disease is a multifactorial disease in which uncontrolled inflammation can lead to corneal epithelium lesions and symptoms of discomfort. The aim of the present study was to evaluate the efficacy of two cyclosporine emulsions in a mouse model of DE with corneal epithelium lesions. Materials and Methods: Six-to 9-week-old female C57BL/6 N mice were housed in a controlledenvironment room to induce DE. Following DE development, mice were instilled with: QD 0.1%CsA cationic emulsion (CaEm), BID 0.05%CsA anionic emulsion (AEm), or left untreated. Aqueous tear production and corneal epithelium lesions were assessed throughout the experiment. At the end of the treatment period, left eyes were sampled, fixed, and stained for histology, while the cornea, conjunctiva, and lacrimal gland of right eyes were sampled for transcriptomic analysis. Results: Corneal lesion scores were reduced by 10.4%, 18.4%, and 10.9% at day 6, 10, and 14, respectively, with CaEm (QD), and by 2.6%, 3.0%, and 5.5% at day 6, 10, and 14, respectively, with AEm (BID). Histology demonstrated that 7 out of 10 DE mice presented moderate to severe ocular lesions, while only 2 and 5 out of 10 mice presented slight to moderate ocular lesions when treated with the CaEm (QD) and AEm (BID), respectively. The transcriptomic profile analysis suggests that a different set of inflammatory genes are modulated in the cornea, conjunctiva, and lacrimal gland upon DE development. In addition, the two emulsions distinctively modulate the gene expression profile. Conclusions: This study demonstrates that both emulsions were effective at reducing corneal lesions, with the CaEm (QD) being slightly better than the AEm (BID). Interestingly, this study suggests that ocular tissues may not respond similarly to a dry environment and that a different set of genes is modulated by the two formulations in the ocular tissues.

Review of Preclinical Outcomes of a Topical Cationic Emulsion of Cyclosporine A for the Treatment of Ocular Surface Diseases

“…61 Compared to AE-CsA, treatment of DED with CE-CsA induced lower CFS scores, but a significant difference was not achieved in all studies. 59,60,64 However, CE-CsA treatment did reduce the occurrence of ocular lesions due to DED, compared to AE-CsA. These results highlight that CE itself can reduce keratitis induced by DED, which can be explained by its anti-inflammatory activity as well as its improved electrostatic interactions with the ocular surface and tear film lipid layer, previously described.…”

“…Effects of CE-CsA and CE alone on signs of DED have also been tested using in vivo mice models. [59][60][61][62][63][64] DED was induced in mice using a controlled environment room with low humidity, as previously described in the literature. 67 Clinically, two Ref.…”

Therapeutic Drugs and Devices for Tackling Ocular Hypertension and Glaucoma, and Need for Neuroprotection and Cytoprotective Therapies

“…Majority of the health authority approved drugs to treat a multitude of diseases that beset animals and humans exert their effects by modulating activity of cellular targets such as enzymes, receptors, ion-channels and transporters. Organic compounds, both naturally occuring (e.g., cyclosporin for dry eye; Daull et al, 2021) and synthetic drugs (e.g., olopatadine for ocular allergies (Sharif, 2020a,b); travoprost/tafluprost Hellberg et al, 2001Hellberg et al, , 2002 and omidenepag isopropyl ester (Kirihara et al, 2018a;Aihara et al, 2020a) to treat OHT/ glaucoma), peptides (e.g., angiotensin-II and bradykinin; Sharif, 2015), antibodies (avastin; ranibizumab; aflibercept; Asahi et al, 2021) and most recently gene-therapy-based (aptamers; Fattal and Bochot, 2006;Khatib and Martin, 2017) medicines (and potential future drugs) have been discovered, characterized and introduced into medical treatment of diseases of the eye.…”

Attrition und Osmokinetik – Zwei Konzepte zur Pathogenese des Trockenen Auges

“…4). Obgleich dabei die Anzahl und ungefähre Lage der Färbungen auf der Augenoberfläche sich im Allgemeinen nicht dramatisch in kurzer Zeit ändern, so Immunomodulatoren wie Steroide, Cyclosporin A [20,21] oder ICAM-1-Inhibitoren [22]. Die Anfänge in der Entwicklung des Trockenen Auges dagegen sind oft subtil und schleichend, vorrübergehende Prodromalstadien sind mehr von Symptomen als vom Vorliegen klinischer Befunde geprägt.…”