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Dry eye disorders are a major health care burden. We previously reported the identification of -methyl--phenyl-6-(2,2,3,3-tetrafluoropropoxy)-1,3,5-triazine-2,4-diamine [cystic fibrosis transmembrane conductance regulator (CFTR)-K267], which activated human wild-type CFTR chloride conductance with EC ∼ 30 nM. Here, we report evidence for CFTR-K267 efficacy in an experimental mouse model of dry eye using a human compatible ophthalmic vehicle. CFTR activation in mice was demonstrated by ocular surface potential difference (OSPD) measurements. Ocular surface pharmacodynamics was measured in tear fluid samples obtained at different times after topical administration of CFTR-K267. Dry eye was produced by lacrimal duct cautery (LDC) and corneal epithelial injury and was assessed by Lissamine green (LG) staining. OSPD measurements demonstrated a hyperpolarization of -8.6 ± 3 mV (standard error of the mean, 5 mice) in response to CFTR-K267 exposure in low chloride solution that was reversed by a CFTR inhibitor. Following single-dose topical administration of 2 nmol CFTR-K267, tear fluid CFTR-K267 concentration was >500 nM for more than 6 h. Following LDC, corneal surface epithelial injury, as assessed by LG staining, was substantially reversed in 10 of 12 eyes receiving 2 nmol CFTR-K267 3 times daily starting on day 2, when marked epithelial injury had already occurred. Improvement was seen in 3 of 12 vehicle-treated eyes. These studies provide evidence in mice for the efficacy of a topical, human use compatible CFTR-K267 formulation in stimulating chloride secretion and reversing corneal epithelial injury in dry eye.
This article was published in the following journal.
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Aberrant epithelial bicarbonate (HCO) secretion caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene is associated with several diseases including cystic fibrosis...
The measurement of regional corneal epithelial thickness and characterization of its behavior in response to changes to corneal architecture are increasingly drawing interest in clinical practice. The...
We have observed noticably weak epithelial attachment in vitamin D receptor knockout mice (VDR KO) undergoing epithelial debridement. We hypothesized that VDR KO negatively affects corneal epithelial ...
The cystic fibrosis transmembrane conductance regulator (CFTR) is a chloride channel central to the development of secretory diarrhea and cystic fibrosis. The oldest CFTR ortholog identified is from d...
The purpose of the study is to determine if SJP-0035 ophthalmic solution is effective in promoting corneal epithelial wound healing in conditions associated with corneal epithelial disorde...
Human serum eye drops have been successfully used in the treatment of severe ocular surface disorders and the enhancement of corneal wound healing. Umbilical cord serum is also proven to b...
The purpose of this study is to determine whether SJP-0035 ophthalmic solution is effective in promoting corneal epithelial wound healing in conditions associated with corneal epithelial d...
The primary aim of the study is to evaluate the clinical response of ST266 treated subjects with persistent corneal epithelial defects after 28 days of therapy. The secondary endpoint is t...
The purpose of this study is to elucidate the appropriate condition of developing cultivated corneal epithelial graft and evaluate the surgical outcome of transplantation of the cultivate...
A type I keratin that is found associated with the KERATIN-3 in the CORNEA and is regarded as a marker for corneal-type epithelial differentiation. Mutations in the gene for keratin-12 have been associated with MEESMANN CORNEAL EPITHELIAL DYSTROPHY.
A type II keratin that is found associated with the KERATIN-12 in the CORNEA and is regarded as a marker for corneal-type epithelial differentiation. Mutations in the gene for keratin-3 have been associated with MEESMANN CORNEAL EPITHELIAL DYSTROPHY.
An autosomal dominant form of hereditary corneal dystrophy due to a defect in cornea-specific KERATIN formation. Mutations in the genes that encode KERATIN-3 and KERATIN-12 have been linked to this disorder.
New blood vessels originating from the corneal veins and extending from the limbus into the adjacent CORNEAL STROMA. Neovascularization in the superficial and/or deep corneal stroma is a sequel to numerous inflammatory diseases of the ocular anterior segment, such as TRACHOMA, viral interstitial KERATITIS, microbial KERATOCONJUNCTIVITIS, and the immune response elicited by CORNEAL TRANSPLANTATION.
A strain of mice widely studied as a model for cystic fibrosis. These mice are generated from embryonic stem cells in which the CFTR (cystic fibrosis transmembrane conductance regulator) gene is inactivated by gene targeting. As a result, all mice have one copy of this altered gene in all their tissues. Mice homozygous for the disrupted gene exhibit many features common to young cystic fibrosis patients, including failure to thrive, meconium ileus, and alteration of mucous and serous glands.
Ophthalmology is the branch of medicine that is devoted to the study and treatment of eye diseases. As well as mild visual defects correctable by lenses, ophthalmology is concerned with glaucoma, uveitis and other serious conditions affecting the eye, ...