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Antibody–drug conjugates (ADCs) are a new class of therapeutic agents designed to target specific antigens on tumor cells, combining the specificity of monoclonal antibodies with the cytotoxicity of chemotherapy agents. ADCs have been available for over a decade, but in gynecological cancers, these agents are relatively new with great promise ahead. More than 80% of ongoing trials in gynecological cancers are evaluating ADCs' safety and efficacy, of which 40% are early-phase trials. Around twenty ADCs are currently under investigation, either alone or in combination with chemotherapies or immune checkpoint inhibitors. Among them, mirvetuximab soravtansine has been recently approved by the Food and Drug Administration (FDA) in platinum-resistant ovarian cancer with high folate-α receptor expression, as a single agent or in combination. Tisotumab vedotin and trastuzumab deruxtecan are also now approved by the FDA in patients with pre-treated cervical and uterine cancers and further investigation is ongoing. Overall, the toxicity profiles of ADCs are acceptable. Ocular toxicity is one of the specific side effects of some ADCs, but most of the cases are manageable with the use of prophylactic steroids and dose adjustments. This review aims to provide an overview of the fundamental and operational features of ADCs and examine the latest and most promising data, with a particular focus on the Canadian viewpoint. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, offering significant improvements in patient survival across various malignancies. However, their use is associated with a broad spectrum of immune-related adverse events (irAEs), including those affecting the eye and its surrounding structures, collectively termed ocular irAEs (OirAEs). Although rare, OirAEs (e.g., keratitis, uveitis, retinal vasculitis, etc.) can significantly impact a patient's quality of life, leading to ocular complications if left untreated. This review provides a comprehensive overview of OirAEs associated with ICIs, including their clinical manifestations, underlying mechanisms, and current management strategies. We delve into the anterior and posterior segment adverse events, highlighting conditions such as dry eye, uveitis, and retinal disorders, as well as neuro-ophthalmic and orbital complications. Furthermore, we discuss the challenges in diagnosing and treating these conditions, particularly given the overlap with other autoimmune and paraneoplastic syndromes. Finally, we identify key knowledge gaps and suggest future research directions aimed at optimizing the management of OirAEs while maintaining the efficacy of cancer therapy. This review underscores the need for increased awareness among clinicians to prevent irreversible ocular damage and enhance patient outcomes. [ABSTRACT FROM AUTHOR]

Background: Platinum-based combination chemotherapy, including cisplatin and carboplatin, are important cytotoxic anti-cancer agents that are widely used to treat various solid tumors. Carboplatin has a similar effect on survival in small cell lung cancer, but generally has a milder toxicity profile when compared with cisplatin. Both may cause moderate or severe neurotoxicity, but ocular neurotoxicity from carboplatin is rarely reported. Case presentation: A 79-year-old man underwent intravenous polychemotherapy (atezolizumab, etoposide, and carboplatin) for small cell lung cancer. One week after the second cycle of chemotherapy, he reported bilateral visual loss as hand motion in both eyes. Dilated fundus examination showed retinal arterial narrowing without hemorrhage, and diffuse choroidal and retinal thinning was observed in an optical coherence tomography scan. Fluorescein angiography revealed significantly delayed circulation without evidence of obstructive lesions. 30-Flicker electroretinogram testing showed a complete absence of cone response in both eyes. The patient's visual acuity aggravated to no light perception in both eyes, even after the cessation of chemotherapy. Conclusions: Carboplatin combination chemotherapy administered at therapeutic doses can result in irreversible visual loss, a side effect that is not widely acknowledged. When using carboplatin, physicians should be aware of its potential ocular toxicity. [ABSTRACT FROM AUTHOR]

An inflammation-resolving polysialic acid-decorated PLGA nanoparticle (PolySia-NP) has been developed to treat geographic atrophy/age-related macular degeneration and other conditions caused by macrophage and complement over-activation. While PolySia-NPs have demonstrated pre-clinical efficacy, this study evaluated its systemic and intraocular safety. PolySia-NPs were evaluated in vitro for mutagenic activity using Salmonella strains and E. coli, with and without metabolic activation; cytotoxicity was evaluated based on its interference with normal mitosis. PolySia-NPs were administered intravenously in CD-1 mice and Sprague Dawley rats and assessed for survival and toxicity. Intravitreal (IVT) administration in Dutch Belted rabbits and non-human primates was assessed for ocular or systemic toxicity. In vitro results indicate that PolySia-NPs did not induce mutagenicity or cytotoxicity. Intravenous administration did not show clastogenic activity, effects on survival, or toxicity. A single intravitreal (IVT) injection and two elevated repeat IVT doses of PolySia-NPs separated by 7 days in rabbits showed no signs of systemic or ocular toxicity. A single IVT inoculation of PolySia-NPs in non-human primates demonstrated no adverse clinical or ophthalmological effects. The demonstration of systemic and ocular safety of PolySia-NPs supports its advancement into human clinical trials as a promising therapeutic approach for systemic and retinal degenerative diseases caused by chronic immune activation. [ABSTRACT FROM AUTHOR]

Studies comparing the ocular toxicity potential between legacy and alternative PFAS are lacking. To address this research gap, zebrafish larvae were exposed to both legacy PFAS (i.e., perfluorooctanesulfonic acid [PFOS] and perfluorooctanoic acid [PFOA]) and their corresponding alternatives (i.e., perfluorobutanesulfonic acid [PFBS] and perfluorobutanoic acid [PFBA]). Alterations in their visual behaviors, such as phototactic and optomotor responses (OMR), were assessed at sublethal concentrations. Gene expression variations in visual function-associated pathways were also measured. Visual behavioral assessment revealed that PFOS exposure resulted in concentration-dependent reductions in phototactic responses at 10–1000 μg/L, with PFOA exerting reduction effects only at 100 mg/L. However, their two alternatives had no effect at all tested concentrations. Following an improved contrast-OMR (C-OMR) assessment, PFOS decreased the OMR to a water flow stimulus at 10, 100, and 1000 μg/L. The gene expression analysis revealed that PFOS exposure markedly downregulated most genes involved in the opsins in the photoreceptor and phototransduction cascade, which explains the observed visual behavior changes well. Our findings indicate that PFOS is the most likely PFAS to cause visual toxicity, with PFOA present but less likely, and their substitutes, PFBS and PFBA, cannot be classified as visually toxic to zebrafish. [ABSTRACT FROM AUTHOR]

Etridiazole (EDZ) is a thiadiazole-containing fungicide commonly used to control Pythium and Phytophthora spp. Although previous studies have shown that EDZ is teratogenic, the exact molecular mechanisms underlying its toxicity remain unknown. In this study, a zebrafish (Danio rerio; ZF) model was used to explore the molecular pathways associated with EDZ toxicity. The whole transcriptome of ZF embryos exposed to 96 h of EDZ was analyzed, along with developmental abnormalities. EDZ-induced malformations were primarily related to the eyes, heart, and growth of the ZF. Compared to untreated ZF, etridiazole-treated ZF had 2882 differentially expressed genes (DEGs), consisting of 1651 downregulated genes and 1231 upregulated genes. Gene ontology enrichment analysis showed that DEGs were involved in biological processes, such as sensory perception, visual perception, sensory organ development, and visual system development, and showed transmembrane transporter and peptidase regulator activities. Metabolism, phototransduction, aminoacyl-tRNA biosynthesis, MAPK signaling pathway, calcium signaling pathway, and vascular smooth muscle contraction were among the most enriched KEGG pathways. The qPCR analyses of the eight random genes were in good agreement with the transcriptome data. These results suggest several putative mechanisms underlying EDZ-induced developmental deformities in ZF. [ABSTRACT FROM AUTHOR]

The presence of contaminants in the environment has increased in recent years, and studies have demonstrated that these contaminants have the ability to penetrate the blood–retinal barrier and directly affect the visual systems of organisms. Zebrafish are recognized as an ideal model for human eye diseases due to their anatomical and functional similarities to the human eye, making them an efficient and versatile organism for studying ocular toxicity caused by environmental contaminants in the field of environmental toxicology. Meanwhile, zebrafish exhibit a diverse repertoire of visually mediated behaviors, and their visual system undergoes complex changes in behavioral responses when exposed to environmental contaminants, enabling rapid assessment of the ocular toxicity induced by such pollutants. Therefore, this review aimed to highlight the effectiveness of zebrafish as a model for examining the effects of environmental contaminants on ocular development. Special attention is given to the visually mediated behavior of zebrafish, which allows for a rapid assessment of ocular toxicity resulting from exposure to environmental contaminants. Additionally, the potential mechanisms by which environmental contaminants may induce ocular toxicity are briefly outlined. [ABSTRACT FROM AUTHOR]

Adenoviruses are the major cause of ocular viral infections worldwide. Currently, there is no approved antiviral treatment for these eye infections. Cyclopentenylcytosine (CPE-C) is an antiviral that has demonstrated activity against more than 20 viruses. The goals of the current study were to determine the in vitro and in vivo antiviral activity of CPE-C as well as its ocular toxicity. Antiviral activity was evaluated in vitro using standard plaque reduction assays to determine the 50% effective concentrations (EC50s) and in vivo in the Ad5/NZW rabbit ocular replication model. Ocular toxicity was determined in uninfected rabbit eyes following topical ocular application. The in vitro EC50s for CPE-C ranged from 0.03 to 0.059 μg/mL for nine adenovirus types that commonly infect the eye. Ocular toxicity testing determined CPE-C to be non-irritating or practically non-irritating by Draize scoring. In vivo, 3% CPE-C topically administered 4X or 2X daily for 7 days to adenovirus-infected eyes demonstrated effective antiviral activity compared with the negative control and comparable antiviral activity to the positive control, 0.5% cidofovir, topically administered twice daily for 7 days. We conclude CPE-C was relatively non-toxic to rabbit eyes and demonstrated potent anti-adenoviral activity in vitro and in vivo. [ABSTRACT FROM AUTHOR]

Background: Different drugs have been approved to reduce the intraocular pressure. However, most of them contain preservatives to maintain sterility and these can be toxic to the ocular surface. The aim was to determine the patterns of use of antiglaucoma agents and ophthalmic preservatives in a group of patients from Colombia. Methods: A cross-sectional study that identified ophthalmic antiglaucoma agents from a population database of 9.2 million. Sociodemographic and pharmacological variables were considered. Descriptive and bivariate analyses were performed. Results: A total of 38,262 patients were identified, with a mean age of 69.2 ± 13.3 years, and 58.6% were women. A total of 98.8% were prescribed antiglaucoma drugs in multidose containers. The most widely used were prostaglandin analogs (59.9%), especially latanoprost (51.6%) and β-blockers (59.2%). A total of 54.7% of patients received combined management, especially with fixed-dose combination (FDC) drugs (41.3%). A total of 94.1% used antiglaucoma drugs with preservatives (benzalkonium chloride, 68.4%). Conclusions: The pharmacological treatment of glaucoma was very heterogeneous, but the most commonly used therapeutic groups were in accordance with the recommendations of clinical practice guidelines but with differences by sex and age. Most of the patients were exposed to preservatives, especially benzalkonium chloride, but the wide use of FDC drugs can minimize toxicity on the ocular surface. [ABSTRACT FROM AUTHOR]

Tamoxifen is a drug used in breast cancer therapy, which inhibits the division of neoplastic cells targeting estrogen receptors. The drug is generally well-tolerated and its use does not cause serious side-effects. The standard dose of the drug is 20 mg once a day for 3 to 5 years. Available epidemiological data have shown that the incidence of ocular toxicity of tamoxifen ranges between 0.9% and 12.0% and increases with higher tamoxifen dose. A rare known complication of tamoxifen use is the development of retinopathy. We present a case of 57-year-old woman presented to an ophthalmologist with decreased visual acuity in her right eye. She has been treated with tamoxifen 20 mg daily for 7 years for breast cancer. Clinical examination and multimodal imaging methods help confirm the diagnosis of unilateral tamoxifen associated retinopathy (TAR). Optical coherence tomography angiography (OCTA) was crucial in the diagnostic process and differential diagnosis, especially in differentiating it from type 2 macular telangiectasias. The correct diagnosis of TAR is very important in deciding the treatment option of tamoxifen. Based on our diagnosis, the oncologist recommended another course of treatment. Tamoxifen therapy was discontinued and switched to letrozole 2.5 mg once a day. The patient attends ophthalmological examination regularly. Visual acuity, OCT and OCTA results remain stable. [ABSTRACT FROM AUTHOR]

Hydroxychloroquine (HCQ) ocular toxicity is rare but severe, and progression can occur even after termination of therapy. Case reports have suggested that a bull's eye maculopathy detected by near-infrared reflectance (NIR) may indicate early HCQ toxicity. This retrospective cross-sectional study evaluated patients treated with HCQ who underwent routine screening with optical coherence tomography (OCT), fundus autofluorescence (FAF) and 10-2 perimetry. NIR images captured alongside OCT were subsequently graded independently by 2 masked graders for the presence of bull's eye maculopathy, and the result was compared to the outcome of the screening. A total of 123 participants (246 eyes) were included, and 101 (90%) were female. The patients' mean age was 55.2 ± 13.8 years. The mean time of HCQ usage was 84.0 ± 72.3 months, and the mean weekly dose was 2327 ± 650 mg. Two eyes showed toxicity in all 3 routine screening exams, with one patient suspending HCQ. The prevalence of bull´s eye lesions in NIR was 13% (33 eyes) with substantial intergrader agreement, a 71.3% specificity and 88.0% negative predictive value for HCQ toxicity. We suggest that NIR changes may be a sign of early HCQ toxicity. The detection of NIR bull´s eye lesions may warrant an increased screening frequency. [ABSTRACT FROM AUTHOR]

Photopharmacological compounds such as azobenzene-based photoswitches have been shown to control the conductivity of ionic channels in a light-dependent manner and are considered a potential strategy to restore vision in patients with end-stage photoreceptor degeneration. Here, we report the effects of DENAQ, a second-generation azobenzene-based photoswitch on retinal ganglion cells (RGC) in canine retinas using multi-electrode array (MEA) recordings (from nine degenerated and six WT retinas). DENAQ treatment conferred increased light sensitivity to RGCs in degenerated canine retinas. RGC light responses were observed in degenerated retinas following ex vivo application of 1 mM DENAQ (n = 6) or after in vivo DENAQ injection (n = 3, 150 μL, 3–10 mM) using 455 nm light at intensities as low as 0.2 mW/cm2. The number of light-sensitive cells and the per cell response amplitude increased with light intensity up to the maximum tested intensity of 85 mW/cm2. Application of DENAQ to degenerated retinas with partially preserved cone function caused appearance of DENAQ-driven responses both in cone-driven and previously non-responsive RGCs, and disappearance of cone-driven responses. Repeated stimulation slowed activation and accelerated recovery of the DENAQ-driven responses. The latter is likely responsible for the delayed appearance of a response to 4 Hz flicker stimulation. Limited aqueous solubility of DENAQ results in focal drug aggregates associated with ocular toxicity. While this limits the therapeutic potential of DENAQ, more potent third-generation photoswitches may be more promising, especially when delivered in a slow-release formulation that prevents drug aggregation. [ABSTRACT FROM AUTHOR]

Ocular surface exposure to nitrogen mustard (NM) leads to severe ocular toxicity which includes the separation of epithelial and stromal layers, loss of endothelial cells, cell death, and severe loss of tissue function. No definitive treatment for mustard gas-induced ocular surface disorders is currently available. The research was conducted to investigate the therapeutic potential of mesenchymal stem cell-conditioned media (MSC-CM) in NM-induced corneal wounds. NM was added to different types of corneal cells, the ocular surface of porcine, and the ocular surface of mice, followed by MSC-CM treatment. NM significantly induced apoptotic cell death, cellular ROS (Reactive oxygen species), and reduced cell viability, metabolic gene expression, and mitochondrial function, and, in turn, delayed wound healing. The application of MSC-CM post NM exposure partially restored mitochondrial function and decreased intracellular ROS generation which promoted cell survival. MSC-CM therapy enhanced wound healing process. MSC-CM inhibited NM-induced apoptotic cell death in murine and porcine corneal tissue. The application of MSC-CM following a chemical insult led to significant improvements in the preservation of corneal structure and wound healing. In vitro, ex vivo, and in vivo results suggest that MSC-CM can potentially provide targeted therapy for the treatment of chemical eye injuries, including mustard gas keratopathy (MGK) which presents with significant loss of vision alongside numerous corneal pathologies. [ABSTRACT FROM AUTHOR]

Delivering high-molecular-weight hydrophobic peptides, such as cyclosporine A, across the corneal epithelium remains a challenge that is complicated by other physio-anatomical ocular structures that limit the ocular bioavailability of such peptides. Transferosomes have previously been used to improve transdermal permeability, and have the potential for improving the ocular corneal permeability of applicable drugs. In this study, transferosomes for the potential ocular delivery of cyclosporine A were investigated. Linoleic acid was evaluated for its effect on the stability of the transferosomes and was substituted for a portion of the cholesterol in the vesicles. Additionally, Span® 80 and Tween® 80 were evaluated for their effect on transferosome flexibility and toxicity to ocular cells as edge activators. Attenuated Total Reflectance–Fourier Transform Infrared spectroscopy (ATF-FTIR), differential scanning calorimetry (DSC), and dynamic light scattering (DLS) were used to evaluate the physicochemical parameters of the blank and the cyclosporine A-loaded transferosomes. Cyclosporine A release and corneal permeability were studied in vitro and in a New Zealand albino rabbit corneal model, respectively. The linoleic acid contributed to improved stability and the nano-size of the transferosomes. The Tween®-based formulation was preferred on the basis of a more favorable toxicity profile, as the difference in their corneal permeability was not significant. There was an initial burst release of cyclosporine A in the first 24 h that plateaued over one week. The Tween®-based formulation had a flux of 0.78 µg/cm2/h. The prepared transferosomes demonstrated biocompatibility in the ocular cell line, adequately encapsulated cyclosporine A, ensured the corneal permeability of the enclosed drug, and were stable over the period of investigation of 4 months at −20 °C. [ABSTRACT FROM AUTHOR]

The ocular surface, comprised of the transparent cornea, conjunctiva, and protective tear film, forms a protective barrier defending deeper structures of the eye from particulate matter and mechanical trauma. This barrier is routinely exposed to a multitude of naturally occurring and engineered nanomaterials (ENM). Metallic ENMs are particularly ubiquitous in commercial products with a high risk of ocular exposure, such as cosmetics and sunscreens. Additionally, there are several therapeutic uses for metallic ENMs owing to their attractive magnetic, antimicrobial, and functionalization properties. The increasing commercial and therapeutic applications of metallic ENMs come with a high risk of ocular exposure with poorly understood consequences to the health of the eye. While the toxicity of metallic ENMs exposure has been rigorously studied in other tissues and organs, further studies are necessary to understand the potential for adverse effects and inform product usage for individuals whose ocular health may be compromised by injury, disease, or surgical intervention. This review provides an update of current literature on the ocular toxicity of metallic ENMs in vitro and in vivo, as well as the risks and benefits of therapeutic applications of metallic ENMs in ophthalmology. [ABSTRACT FROM AUTHOR]

Background: Fungal ocular infections can cause serious consequences, despite their low incidence. It has been reported that Posaconazole (PSC) is used in the treatment of fungal infections in different ocular tissues by diluting the oral suspension, and successful results were obtained despite low ocular permeation. Therefore, we optimized PSC-loaded ocular micelles and demonstrated that the permeation/penetration of PSC in ocular tissues was enhanced. Methods: The micellar-based in situ gels based on the QbD approach to increase the ocular bioavailability of PSC were developed. Different ratios of Poloxamer 407 and Poloxamer 188 were chosen as CMAs. Tsol/gel, gelling capacity and rheological behavior were chosen as CQA parameters. The data were evaluated by Minitab 18, and the formulations were optimized with the QbD approach. The in vitro release study, ocular toxicity, and anti-fungal activity of the optimized formulation were performed. Results: Optimized in situ gel shows viscoelastic property and becomes gel form at physiological temperatures even when diluted with the tear film. In addition, it has been shown that the formulation had high anti-fungal activity and did not have any ocular toxicity. Conclusions: In our previous studies, PSC-loaded ocular micelles were developed and optimized for the first time in the literature. With this study, the in situ gels of PSC for ocular application were developed and optimized for the first time. The optimized micellar-based in situ gel is a promising drug delivery system that may increase the ocular permeation and bioavailability of PSC. [ABSTRACT FROM AUTHOR]

Retinal infection with Toxoplasma gondii--ocular toxoplasmosis--is a common cause of vision impairment worldwide. Pathology combines parasite-induced retinal cell death and reactive intraocular inflammation. Müller glial cells, which represent the supporting cell population of the retina, are relatively susceptible to infection with T. gondii. We investigated expression of long non-coding RNAs (lncRNAs) with immunologic regulatory activity in Müller cells infected with virulent T. gondii strains--GT1 (haplogroup 1, type I) and GPHT (haplogroup 6). We first confirmed expression of 33 lncRNA in primary cell isolates. MIO-M1 human retinal Müller cell monolayers were infected with T. gondii tachyzoites (multiplicity of infection = 5) and harvested at 4, 12, 24, and 36 h post-infection, with infection being tracked by the expression of parasite surface antigen 1 (SAG1). Significant fold-changes were observed for 31 lncRNAs at one or more time intervals. Similar changes between strains were measured for BANCR, CYTOR, FOXD3-AS1, GAS5, GSTT1-AS1, LINC-ROR, LUCAT1, MALAT1, MIR22HG, MIR143HG, PVT1, RMRP, SNHG15, and SOCS2-AS1. Changes differing between strains were measured for APTR, FIRRE, HOTAIR, HOXD-AS1, KCNQ1OT1, LINC00968, LINC01105, lnc-SGK1, MEG3, MHRT, MIAT, MIR17HG, MIR155HG, NEAT1, NeST, NRON, and PACER. Our findings suggest roles for lncRNAs in regulating retinal Müller cell immune responses to T. gondii, and encourage future studies on lncRNA as biomarkers and/or drug targets in ocular toxoplasmosis. [ABSTRACT FROM AUTHOR]

The incorporation of functional groups endows graphene oxide (GO) with different surface charges, which plays important roles in biological interactions with cells. However, the effect of surface charge of GO derivatives on ocular biocompatibility has not been fully elucidated. Previously, we found that positively, negatively and neutrally charged PEGylated GO (PEG-GO) nanosheets exerted similar effect on the viability of ocular cells. In this work, we performed in vitro and in vivo studies to comprehensively study the effect of surface charge of PEG-GO on ocular compatibility. The in vitro results showed that the cellular uptake efficacy of negatively charged PEG-GO nanosheets was significantly decreased compared with positively charged and neutrally charged analogs. However, three kinds of PEG-GO nanosheets produced similar amounts of intracellular reactive oxygen species and showed similar influence on mitochondrial membrane potential. By analysis of global gene expression profiles, we found that the correlation coefficients between three kinds of PEG-GO-treated cells were more than 0.98. Furthermore, in vivo results showed that all these PEG-GO nanosheets had no significant toxicity to ocular structure and function. Taken together, our work suggested that surface charge of PEG-GO exerted negligible effect on its ocular compatibility, except for the cellular uptake. Our work is conducive to understanding the relationship between surface charge and biocompatibility of GO derivatives. [ABSTRACT FROM AUTHOR]

Animal models are used for preclinical toxicity studies, and the need for in vitro alternative methods has been strongly raised. Our study aims to elucidate the potential mechanism of change in EGR1 expression under situations of toxic injury and to develop an Egr1 promoter–luciferase gene reporter assay for an in vitro alternative method for toxicity prediction in drug discovery. We first found an increase in early growth response-1 (EGR1) mRNA/protein expressions in the liver and kidney of cisplatin-treated injured rats. Additionally, the EGR1 protein level was also elevated under situations of ocular injury after sodium lauryl sulfate (SLS) eye drops. These in vivo observations on injury-related EGR1 induction were confirmed by in vitro studies, where human corneal epithelial cells were treated with representative irritants (SLS and benzalkonium chloride) and 17 chemicals having different UN GHS irritant categories. Additionally, our results suggest the involvement of ERK, JNK, p38 MAPK pathways in EGR1 elevation in response to gamma-butyrolactone-induced injury. As EGR1 is considered to be a pivotal factor in proliferation and regeneration, siRNA-mediated knockdown of Egr1 promoted cytotoxic potential through a delay of injury-related recovery. More importantly, the elevation of promoter activities was observed by various irritants in cells transfected with Egr1 promoter-reporter vector. In conclusion, Egr1 can be a potential biomarker in a promoter-reporter system to improve the accuracy of in vitro predictions for ocular irritation. [ABSTRACT FROM AUTHOR]

Stem cell factor (SCF) and its receptor, cKIT, are novel regulators of pathological neovascularization in the eye, which suggests that inhibition of SCF/cKIT signaling may be a novel pharmacological strategy for treating neovascular age-related macular degeneration (AMD). This study evaluated the therapeutic potential of a newly developed fully human monoclonal antibody targeting cKIT, NN2101, in a murine model of neovascular AMD. In hypoxic human endothelial cells, NN2101 substantially inhibited the SCF-induced increase in angiogenesis and activation of the cKIT signaling pathway. In a murine model of neovascular AMD, intravitreal injection of NN2101 substantially inhibited the SCF/cKIT-mediated choroidal neovascularization (CNV), with efficacy comparable to aflibercept, a vascular endothelial growth factor inhibitor. A combined intravitreal injection of NN2101 and aflibercept resulted in an additive therapeutic effect on CNV. NN2101 neither caused ocular toxicity nor interfered with the early retinal vascular development in mice. Ocular pharmacokinetic analysis in rabbits indicated that NN2101 demonstrated a pharmacokinetic profile suitable for intravitreal injection. These findings provide the first evidence of the potential use of the anti-cKIT blocking antibody, NN2101, as an alternative or additive therapeutic for the treatment of neovascular AMD. [ABSTRACT FROM AUTHOR]

In 2020, a global pandemic was declared following the spread of SARS-CoV-2, the pathogen responsible for COVID-19. The risk of infection is high due to the ease of transmission, which can occur orally, through droplets, or via contact with contaminated surfaces and objects. It has also been demonstrated that the ocular surface can constitute a transmission route, especially in hospital settings, where health care workers can become a dangerous source of infection. In order to increase prevention and reduce the spread of the virus on the ocular surface, the antiviral activity of already-marketed eye drops against SARS-CoV-2 was evaluated. Iodim, Ozodrop, Septavis, and Dropsept were tested against SARS-CoV-2 in plaque-assay experiments at different stimulation times. Furthermore, the expression levels of early and late genes were evaluated through molecular assays. Results indicated that three of the four ophthalmic solutions showed a considerable dose-dependent inhibition of viral replication, highlighting their use as potential antiviral drugs against SARS-CoV-2 and preventing other ocular infections. [ABSTRACT FROM AUTHOR]

Several RNA viruses, including SARS-CoV-2, can infect or use the eye as an entry portal to cause ocular or systemic diseases. Povidone-Iodine (PVP-I) is routinely used during ocular surgeries and eye banking as a cost-effective disinfectant due to its broad-spectrum antimicrobial activity, including against viruses. However, whether PVP-I can exert antiviral activities in virus-infected cells remains elusive. In this study, using Zika (ZIKV) and Chikungunya (CHIKV) virus infection of human corneal and retinal pigment epithelial cells, we report antiviral mechanisms of PVP-I. Our data showed that PVP-I, even at the lowest concentration (0.01%), drastically reduced viral replication in corneal and retinal cells without causing cellular toxicity. Antiviral effects of PVP-I against ZIKV and CHIKV were mediated by direct viral inactivation, thus attenuating the ability of the virus to infect host cells. Moreover, one-minute PVP-I exposure of infected ocular cells drastically reduced viral replication and the production of infectious progeny virions. Furthermore, viral-induced (CHIKV) expression of inflammatory genes (TNF-α, IL-6, IL-8, and IL1β) were markedly reduced in PVP-I treated corneal epithelial cells. Together, our results demonstrate potent antiviral effects of PVP-I against ZIKV and CHIKV infection of ocular cells. Thus, a low dose of PVP-I can be used during tissue harvesting for corneal transplants to prevent potential transmission of RNA viruses via infected cells. [ABSTRACT FROM AUTHOR]

Dry eye disease (DED) is one of the most common ocular surface disorders characterised by a deficiency in quality and/or quantity of the tear fluid. Due to its multifactorial nature involving several inter-related underlying pathologies, it can rapidly accelerate to become a chronic refractory condition. Therefore, several therapeutic interventions are often simultaneously recommended to manage DED efficiently. Typically, artificial tear supplements are the first line of treatment, followed by topical application of medicated eyedrops. However, the bioavailability of topical eyedrops is generally low as the well-developed protective mechanisms of the eye ensure their rapid clearance from the precorneal space, thus limiting ocular penetration of the incorporated drug. Moreover, excipients commonly used in eyedrops can potentially exhibit ocular toxicity and further exacerbate the signs and symptoms of DED. Therefore, formulation development of topical eyedrops is rather challenging. This review highlights the challenges typically faced in eyedrop development, in particular, those intended for the management of DED. Firstly, various artificial tear supplements currently on the market, their mechanisms of action, as well as their application, are discussed. Furthermore, formulation strategies generally used to enhance ocular drug delivery, their advantages and limitations, as well as their application in commercially available DED eyedrops are described. [ABSTRACT FROM AUTHOR]

The glycoprotein disorders are a group of lysosomal storage diseases (α-mannosidosis, aspartylglucosaminuria, β-mannosidosis, fucosidosis, galactosialidosis, sialidosis, mucolipidosis II, mucolipidosis III, and Schindler Disease) characterized by specific lysosomal enzyme defects and resultant buildup of undegraded glycoprotein substrates. This buildup causes a multitude of abnormalities in patients including skeletal dysplasia, inflammation, ocular abnormalities, liver and spleen enlargement, myoclonus, ataxia, psychomotor delay, and mild to severe neurodegeneration. Pharmacological treatment options exist through enzyme replacement therapy (ERT) for a few, but therapies for this group of disorders is largely lacking. Hematopoietic cell transplant (HCT) has been explored as a potential therapeutic option for many of these disorders, as HCT introduces functional enzyme-producing cells into the bone marrow and blood along with the engraftment of healthy donor cells in the central nervous system (presumably as brain macrophages or a type of microglial cell). The outcome of HCT varies widely by disease type. We report our institutional experience with HCT as well as a review of the literature to better understand HCT and outcomes for the glycoprotein disorders. [ABSTRACT FROM AUTHOR]

Dietary vitamin A/all-trans retinol/ROL plays a critical role in human vision. ROL circulates bound to the plasma retinol-binding protein (RBP4) as RBP4-ROL. In the eye, the STRA6 membrane receptor binds to circulatory RBP4 and internalizes ROL. STRA6 is, however, not expressed in systemic tissues, where there is high affinity RBP4 binding and ROL uptake. We tested the hypothesis that the second retinol binding protein 4 receptor 2 (Rbpr2), which is highly expressed in systemic tissues of zebrafish and mouse, contains a functional RBP4 binding domain, critical for ROL transport. As for STRA6, modeling and docking studies confirmed three conserved RBP4 binding residues in zebrafish Rbpr2. In cell culture studies, disruption of the RBP4 binding residues on Rbpr2 almost completely abolished uptake of exogenous vitamin A. CRISPR-generated rbpr2-RBP4 domain zebrafish mutants showed microphthalmia, shorter photoreceptor outer segments, and decreased opsins, which were attributed to impaired ocular retinoid content. Injection of WT-Rbpr2 mRNA into rbpr2 mutant or all-trans retinoic acid treatment rescued the mutant eye phenotypes. In conclusion, zebrafish Rbpr2 contains a putative extracellular RBP4-ROL ligand-binding domain, critical for yolk vitamin A transport to the eye for ocular retinoid production and homeostasis, for photoreceptor cell survival. [ABSTRACT FROM AUTHOR]

Background: The etiology and the mechanism behind atropine treatment of progressive myopia are still poorly understood. Our study addressed the role of scleral and choroidal fibroblasts in myopia development and atropine function. Methods: Fibroblasts treated in vitro with atropine or 7-methylxanthine were tested for ECM production by Western blotting. Corneal epithelial cells were treated with atropine in the presence or absence of colostrum or fucosyl-lactose, and cell survival was evaluated by the MTT metabolic test. Results: Atropine and 7-methyl-xanthine stimulated collagen I and fibronectin production in scleral fibroblasts, while they inhibited their production in choroidal fibroblasts. Four days of treatment with atropine of corneal epithelial cells significantly decreased cell viability, which could be prevented by the presence of colostrum or fucosyl-lactose. Conclusions: Our results show that atropine may function in different ways in different eye districts, strengthening the scleral ECM and increasing permeability in the choroid. The finding that colostrum or fucosyl-lactose attenuate the corneal epithelial toxicity after long-term atropine treatment suggests the possibility that both compounds can efficiently blunt its toxicity in children subjected to chronic atropine treatment. [ABSTRACT FROM AUTHOR]

Anti-glaucoma eye drop treatment often induces dry eyes and can lead to poor medication adherence. This study aimed to investigate the effects of 3% diquafosol sodium eye drops on tear function and the ocular surface epithelium in Sod1−/− mice after treatment with anti-glaucoma eye drops. The mice were divided into four groups: group 1, control group; group 2, anti-glaucoma eye drop; group 3, anti-glaucoma eye drops followed by a secretagogue eye drop (3% diquafosol); and group 4, simultaneous anti-glaucoma and secretagogue eye drop. Mice underwent assessments of tear quantity, tear film breakup time, and vital staining score. Mice in groups 3 and 4 showed significantly better tear stability and lower corneal staining scores than mice in group 2 after eye drop instillations (p < 0.05). Mice in group 4 showed significantly better tear stability, lower corneal staining scores, and higher goblet cell densities than those in group 1 after eye drop instillations (p < 0.05). The conjunctival epithelium showed stratification and abundance of Muc5AC-positive goblet cells in group 4, whereas thinning with desquamation was observed with a few goblet cells in group 2. Thus, simultaneous administration of 3% diquafosol sodium eye drops with topical anti-glaucoma drops showed favorable effects on tear stability and the corneal epithelium against the ocular surface toxicity inflicted by the anti-glaucoma eye drops. [ABSTRACT FROM AUTHOR]

Diabetic retinopathy (DR) is an ocular complication of diabetes mellitus (DM). International Diabetic Federations (IDF) estimates up to 629 million people with DM by the year 2045 worldwide. Nearly 50% of DM patients will show evidence of diabetic-related eye problems. Therapeutic interventions for DR are limited and mostly involve surgical intervention at the late-stages of the disease. The lack of early-stage diagnostic tools and therapies, especially in DR, demands a better understanding of the biological processes involved in the etiology of disease progression. The recent surge in literature associated with NOD-like receptors (NLRs) has gained massive attraction due to their involvement in mediating the innate immune response and perpetuating inflammatory pathways, a central phenomenon found in the pathogenesis of ocular diseases including DR. The NLR family of receptors are expressed in different eye tissues during pathological conditions suggesting their potential roles in dry eye, ocular infection, retinal ischemia, cataract, glaucoma, age-related macular degeneration (AMD), diabetic macular edema (DME) and DR. Our group is interested in studying the critical early components involved in the immune cell infiltration and inflammatory pathways involved in the progression of DR. Recently, we reported that NLRP3 inflammasome might play a pivotal role in the pathogenesis of DR. This comprehensive review summarizes the findings of NLRs expression in the ocular tissues with special emphasis on its presence in the retinal microglia and DR pathogenesis. [ABSTRACT FROM AUTHOR]

The transcription factor PAX6 is essential in ocular development in vertebrates, being considered the master regulator of the eye. During eye development, it is essential for the correct patterning and formation of the multi-layered optic cup and it is involved in the developing lens and corneal epithelium. In adulthood, it is mostly expressed in cornea, iris, and lens. PAX6 is a dosage-sensitive gene and it is highly regulated by several elements located upstream, downstream, and within the gene. There are more than 500 different mutations described to affect PAX6 and its regulatory regions, the majority of which lead to PAX6 haploinsufficiency, causing several ocular and systemic abnormalities. Aniridia is an autosomal dominant disorder that is marked by the complete or partial absence of the iris, foveal hypoplasia, and nystagmus, and is caused by heterozygous PAX6 mutations. Other ocular abnormalities have also been associated with PAX6 changes, and genotype-phenotype correlations are emerging. This review will cover recent advancements in PAX6 regulation, particularly the role of several enhancers that are known to regulate PAX6 during eye development and disease. We will also present an updated overview of the mutation spectrum, where an increasing number of mutations in the non-coding regions have been reported. Novel genotype-phenotype correlations will also be discussed. [ABSTRACT FROM AUTHOR]

Simple Summary: Recently, the emergence of cross-beaks has been reported in several domestic chickens. Despite several candidate genes, bone morphogenetic protein 4 (BMP4) has been suggested as responsible for chicken cross-beaks. The subtypes of the morphology term, etiopathogenesis, and the relationship of the candidate BMP4 gene to cross-beaks are not yet known. The objective of this study was to describe the subtypes of cross-beaks by left or right and upper and lower jaw bones and to figure out the relationship between BMP4 and the development of craniofacial bones in Huiyang bearded chickens. Bird beaks are important for biological purposes such as food intake, removing parasites, and defining phenotypic attributes. Cross-beaks are a threat to poultry health and are harmful to productivity, wasting some units in the poultry industry. However, there is still limited research on subtypes of cross-beaks and the genetic basis of cross-beaks as well. Here, we described the subtypes of cross-beaks in terms of left or right and upper or lower jaw bones. We evaluated the impact of cross-beaks on craniofacial bones and figured out the relationship between bone morphogenetic protein 4 (BMP4) and the development of craniofacial bones in Huiyang bearded chickens. We identified five typical subtypes of cross-beaks by morphological assessment and X-ray scanning. We found that cross-beaks caused certain changes in the facial bone morphology, including changes to the length and width of the bone around the ocular area (p < 0.05). The relative expressions of BMP4 in lacrimal, mandible, premaxilla, frontal, and parietal bones were significantly higher in the severe cross-beak group, followed by that of the medium cross-beak group, weak cross-beak group, and control group (p < 0.05). Overall, we constructed a generally applicable method to classify cross-beaks in term of the angle. The skeleton around the ocular area was affected by the cross-beak. The expression levels of BMP4 in craniofacial bones may provide insight to potential role of BMP4 in the development of cross-beaks. [ABSTRACT FROM AUTHOR]

Bacterial keratitis is an ocular infection that can lead to severe visual disability. Staphylococcus aureus is a major pathogen of the eye. We recently demonstrated the strong antimicrobial activity of LyeTxI-b, a synthetic peptide derived from a Lycosa erithrognatha toxin. Herein, we evaluated a topical formulation (eye drops) containing LyeTxI-b to treat resistant bacterial keratitis. Keratitis was induced with intrastromal injection of 4 × 105 cells (4 µL) in New Zealand female white rabbits. Minimum inhibitory concentration (MIC) and biofilm viability were determined. LyeTxI-b ocular toxicity was evaluated through chorioallantoic membrane and Draize tests. One drop of the formulation (LyeTxI-b 28.9 µmol/L +0.5% CMC in 0.9% NaCl) was instilled into each eye four times a day, for a week. Slit-lamp biomicroscopy analysis, corneal histopathological studies and cellular infiltrate quantification through myeloperoxidase (MPO) and N-acetylglucosaminidase (NAG) detection were performed. LyeTxI-b was very effective in the treatment of keratitis, with no signs of ocular toxicity. Planktonic bacteria MIC was 3.6 µmol/L and LyeTxI-b treatment reduced biofilm viability in 90%. LyeTxI-b eliminated bacteria and reduced inflammatory cellular activity in the eyes. Healthy and treated animals showed similar NAG and MPO levels. LyeTxI-b is a potent new drug to treat resistant bacterial keratitis, showing effective antimicrobial and anti-inflammatory activity. [ABSTRACT FROM AUTHOR]