Glaucoma is associated with ocular hypertension, and lowering intraocular pressure is the primary objective of current therapies. Recent studies have established a key role for Schlemm's canal endothelium in this pressure increase and have shown that it has a unique, lymphatic-like hybrid phenotype characterized by expression of the lymphatic transcription factor PROX1. However, the functional importance of this hybrid phenotype in the adult canal remains unclear, as long-term studies have been limited by systemic requirements for lymphatic gene expression and a lack of Schlemm's canal-specific animal models. Here, we designed and validated a strategy using 4OH-tamoxifen-loaded nanocarriers to generate targeted, Schlemm's canal-specific Prox1 knockout mice that specifically lacked lymphatic characteristics in the canal endothelium. Within four weeks, intraocular pressure was significantly elevated, and ocular hypertension was maintained for at least 24 weeks. Unlike lymphatic vessels, which degenerate following Prox1 deletion, Schlemm's canal persisted but reverted to a less functional vein-like phenotype with no change in size or morphology. Together, these findings demonstrate the utility of nanocarrier-mediated tamoxifen delivery and establish the importance of the Schlemm's canal lymphatic-like phenotype in intraocular pressure regulation, providing targets for future glaucoma therapies and a mouse model of adult-onset ocular hypertension.

Purpose: The objective of this study was to engineer and optimize a mucoadhesive, positively charged stearylamine-enriched liposomal platform, termed Aminosomes, to circumvent the biophysical barriers limiting the ocular bioavailability of Brimonidine Tartrate (BT), an alpha-2 adrenergic receptor agonist for glaucoma management. Methods: Aminosomes were synthesized using a tailored ethanol injection technique and optimized via a 3[2] × 2[1] full factorial design. Molecular integrity and crystallinity were assessed using Fourier-transform infrared spectroscopy (FTIR) and X-ray diffraction (XRD). The mucoadhesive potential was validated through a mucin interaction assay based on zeta potential shifts. In vitro release kinetics were evaluated using the dialysis membrane diffusion technique, while the therapeutic potential and ocular safety were validated through in vivo pharmacodynamic profiling of intraocular pressure (IOP) reduction, alongside comprehensive biocompatibility assessments via Draize irritancy protocol and histopathological examination. Results: The optimized Aminosomes exhibited nanometric dimensions, monodisperse size distribution, robust positive surface charge, and superior drug loading. FTIR and XRD analyses confirmed the chemical compatibility of the formulation components, as well as the successful encapsulation of BT and its transition to an amorphous state within the lipidic matrix. The mucoadhesion test demonstrated a high binding affinity for mucin. The in vitro release profile demonstrated a sustained-release pattern (78.8% over 12 h). Non-compartmental pharmacodynamic analysis of IOP-reduction data revealed a 2.8-fold increase in AUC0-24h, 3.5-fold extension in t1/2, and 5.2-fold prolongation in mean residence time (MRT) relative to the standard solution. Conclusions: The optimized Aminosomes demonstrated superior mucoadhesive anchoring, enhanced and sustained therapeutic flux without inducing ocular toxicity, offering a robust strategy for enhancing the pharmacodynamics of BT.

Background: To evaluate the effects of a preservative-free artificial tear formulation containing trehalose, sodium hyaluronate, and N-acetyl-aspartyl-glutamate (NAAGA) on ocular surface parameters and quality of life in patients with primary open-angle glaucoma (POAG) treated with preserved versus preservative-free prostaglandin analogues. Methods: For this prospective, observational clinical study, thirty-eight patients (76 eyes) with POAG receiving stable topical prostaglandin therapy were enrolled and divided into two groups: preserved prostaglandins (Group 1, n = 44) and preservative-free prostaglandins (Group 2, n = 32). All patients received adjunctive preservative-free artificial tears (trehalose, sodium hyaluronate, NAAGA) three times daily for one month. Assessments at baseline (T0) and 1 month (T1) included best-corrected visual acuity (BCVA), intraocular pressure (IOP), contrast sensitivity, Schirmer test, tear break-up time (BUT), Efron grading scale, Ocular Surface Disease Index (OSDI), visual field (VF) indices (Mean Deviation (MD), Pattern Standard Deviation (PSD), Visual Field Index (VFI)), and quality of life (QoL) measured using Visual Analogue Scales (VAS). Results: After 1 month, both groups demonstrated significant improvement in ocular surface parameters. Schirmer test increased by approximately 4-5 mm (p = 0.001 in both groups), and BUT improved by 5 s (p = 0.001 in both groups). OSDI scores significantly decreased (Group 1: -18.5; Group 2: -23; p = 0.001 for both), and Efron grading significantly improved (p = 0.001 in both groups). Artificial tears-related QoL markedly increased in both groups (p = 0.001), while pathology-related QoL remained unchanged. IOP showed a modest but significant reduction in both groups (Group 1 p = 0.011; Group 2 p = 0.003), without intergroup differences. VFI significantly improved in both groups from T0 to T1 (Group 1 p = 0.013; Group 2 p = 0.04). Group 1 also showed an improvement in terms of PSD (p = 0.025). Conclusions: Adjunctive treatment with preservative-free artificial tears containing trehalose, sodium hyaluronate, and NAAGA significantly improved tear film stability VF indexes, ocular surface signs and symptoms, and patient-reported QoL in POAG patients treated with prostaglandins, regardless of preservative status. Routine ocular surface optimization should be considered an integral component of comprehensive glaucoma management.

Background/Objectives: Rho-associated protein kinase inhibitors reduce intraocular pressure (IOP) by enhancing aqueous humor outflow through the trabecular meshwork-Schlemm's canal pathway. However, it remains unclear whether the fixed-dose combination of ripasudil hydrochloride hydrate and brimonidine tartrate (GLAALPHA) enhances conventional aqueous outflow in vivo. Methods: This single-center randomized clinical trial included healthy adult volunteers who received GLAALPHA, a brimonidine tartrate-brinzolamide fixed-dose combination (Ailamide), or brimonidine tartrate monotherapy (Aiphagan) in a crossover sequence. The aqueous column width in the episcleral veins was assessed at baseline and at 2 h (primary outcome) and 8 h using hemoglobin video imaging. Results: Among 24 participants, analyses included 23 GLAALPHA-treated eyes, 21 Ailamide-treated eyes, and 22 Aiphagan-treated eyes. Two hours after instillation, the aqueous column width significantly increased from baseline only in the GLAALPHA group (p = 0.002). The percent increase in the aqueous column width at 2 h was significantly greater with GLAALPHA than with Ailamide (p = 0.039) and not significantly different between GLAALPHA and Aiphagan (p = 0.114). At 8 h, the aqueous column width did not differ from the baseline in any groups. Conclusions: In healthy adult eyes, GLAALPHA significantly increased the aqueous column width in the episcleral veins 2 h after instillation, indicating enhanced conventional aqueous outflow. These findings provide evidence that GLAALPHA promotes trabecular outflow beyond the effects of brimonidine tartrate-containing comparators and offer mechanistic insights into its action.

Purpose: Evidence on the safety of single-joint isometric exercises of the lower legs remains limited. Thus, the aims of this study were to examine intraocular pressure (IOP) and retinal vessel responses during a 1 min isometric knee extension task and to assess potential sex-related differences. Materials and Methods: This prospective, parallel-group, quasi-experimental exploratory trial enrolled 43 healthy young adults (22 males and 21 females; age range: 19-35 years), who performed a 1 min sustained maximal-effort isometric knee extension task. The cardiovascular response, IOP, and retinal vessel diameters were assessed. Results: The isometric task increased fatigue, heart rate, systolic blood pressure (SBP), and mean arterial pressure in both sexes (p < 0.05), with males exhibiting a significantly greater rise in SBP than females (p < 0.05). A significant reduction in IOP was observed only in males (p < 0.05). Central retinal arteriolar equivalent decreased in both sexes (p < 0.05), whereas central retinal venular equivalent (CRVE) increased exclusively in females (p < 0.05). Despite the difference in the CRVE response, both sexes exhibited a comparably reduced arteriolar-to-venular diameter ratio (p < 0.05). Conclusions: To sum up, the isometric maximal-effort knee extension exercise increased cardiovascular loads in both sexes, with males showing a greater SBP rise and a reduction in IOP. Although retinal microvascular responses were sex specific, both sexes showed a similar reduction in the arteriolar-to-venular diameter ratio, indicating a consistent shift in microvascular regulation.

This retrospective study evaluated real-world outcomes of standalone iDose TR intracameral travoprost implant administration. Sixty-five consecutive standalone iDose TR implantations performed by a single surgeon were analyzed. Patients were pseudophakic, had a diagnosis of open-angle glaucoma (OAG) or ocular hypertension (OHT), and had a history of a prior non-filtering glaucoma procedure (e.g., selective laser trabeculoplasty [SLT] or bimatoprost intracameral implant) performed beyond the preceding 6 months. Intraocular pressure (IOP) and medications were measured for 12 months postoperatively. Subgroup analysis was stratified by history of SLT treatment and glaucoma severity. If target IOP was not attained, secondary minimally invasive glaucoma surgery was performed instead of reinitiating or adding medication, according to the surgeon's standard practice. The analysis was by intention to treat. At 12 months, mean IOP reduced significantly to 14.0 ± 2.9 mmHg from a baseline of 20.0 ± 4.0 mmHg (-28%, p < 0.001). Eyes with IOPs ≤ 18, ≤15, and ≤12 mmHg increased significantly vs. baseline (36.9% to 92.3%, 10.8% to 73.8%, and 3.1% to 35.4%, respectively; all p < 0.001), and 89.2% of the eyes were medication-free vs. 87.7% preoperatively. Mean 12-month IOP reduction showed nonsignificant differences between eyes with or without prior SLT (-26% and -31%, respectively; p = 0.907) and among mild/OHT, moderate, or severe glaucoma eyes (-28%, -23%, and -34%, respectively; p = 0.085). Postoperatively, one case each of transient corneal edema and retinal edema were observed, which self-resolved without sequelae. Thus, standalone travoprost implant administration significantly reduced IOP over 12 months in OAG and OHT, while maintaining a low medication burden. Similar IOP reductions were observed regardless of prior SLT treatment and glaucoma severity.

The study aimed to investigate the safety, optimal biologic dose, and preliminary efficacy of topical neostigmine ophthalmic solution (TNOS) in myasthenia gravis (MG) patients with ptosis. A dose-escalation study comprising cohorts of three patients in each step was performed. The first cohort received 1.5 mg/mL TNOS and was evaluated for safety and efficacy. Then, the subsequent cohorts received the selected dose of TNOS according to the safety and efficacy protocols to determine the optimal biologic dose. Vital signs, visual acuity, intraocular pressure, pupillary size, slit-lamp examinations, and abnormal ocular symptoms were recorded as safety measures. Vertical palpebral fissure and self-reported alleviation of ptosis were investigated as efficacy measures. No systemic or ocular adverse effects were observed in any participant. Vertical palpebral fissure increased by more than 2 mm in 83.3% and 33.3% of patients receiving 1.5 and 1.0 mg/mL TNOS, respectively. The 1.5 mg/mL TNOS significantly increased vertical palpebral fissure from baseline (maximal mean difference 3.30 mm; 95% confidence interval 2.32 to 4.27; p < 0.001). All participants in the 1.5 mg/mL group and 33.3% in the 1.0 mg/mL group reported ptosis alleviation. The 1.5 mg/mL TNOS was considered the optimal biologic dose for alleviating myasthenic ptosis without adverse events.

Glaucoma is a leading cause of irreversible blindness worldwide, characterized by progressive optic neuropathy commonly associated with elevated intraocular pressure (IOP). The trabecular meshwork (TM) is a critical regulator of aqueous humor outflow, and its biological and biomechanical properties directly influence IOP homeostasis. In glaucomatous eyes and in response to various glaucomatous stimuli, TM cells form cross-linked actin networks (CLANs), a special geodesic actin structure. CLANs alter cytoskeletal dynamics, increase cell stiffness, and impair TM function. This review summarizes past and recent research of CLANs, including their inducers, effects on the TM, and role in glaucoma pathogenesis, as well as suggests some future research directions.

Mitochondrial dysfunction plays a critical role in glaucomatous trabecular meshwork (TM) degeneration, whereas increasing intracellular nicotinamide adenine dinucleotide (NAD[+]) levels can restore mitochondrial homeostasis, offering therapeutic benefits for glaucoma. We propose that intracellular NAD[+] can be boosted by promoting NAD[+] biosynthesis through the co-delivery of nicotinamide (NAM), an NAD[+] precursor, and the gene encoding nicotinamide mononucleotide adenylyltransferase 1 (Nmnat1), the rate-limiting enzyme for NAD[+] biosynthesis that consumes NAM. To achieve high gene transfection efficiency, the Nmnat1 gene was encapsulated in a multifunctional lipid nanoparticle (Nmnat1-LNPs). The combination of Nmnat1-LNPs and NAM synergistically reversed mitochondrial dysfunction in primary human trabecular meshwork cells (HTMCs) model. We then developed a new annular sector-shaped microneedle patch (AS-MNs), enabling localized delivery of Nmnat1-LNPs and NAM to the TM. Following application, Nmnat1-LNPs and NAM dual-loaded AS-MNs (Dual@AS-MNs) significantly enhanced the bioavailability of both the Nmnat1 gene and NAM in the TM tissue, leading to a marked reduction in intraocular pressure and alleviation of TM fibrosis in a dexamethasone-induced mice model of glaucoma, highlighting its therapeutic potential. This study presents the first development of an annular sector-shaped microneedle patch as a targeted TM drug delivery platform, and offers a promising new combinatorial strategy for glaucoma treatment.