Outflow Pathway Research Articles

Matrix Metalloproteinases and Glaucoma Treatment.

Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes that degrade extracellular matrix (ECM) components such as collagen and have important roles in multiple biological processes, including development and tissue remodeling, both in health and disease. The activity of MMPs is influenced by the expression of MMPs and tissue inhibitors of metalloproteinase (TIMPs). In the eye, MMP-mediated ECM turnover in the juxtacanalicular region of the trabecular meshwork (TM) reduces outflow resistance in the conventional outflow pathway and helps maintain intraocular pressure (IOP) homeostasis. An imbalance in the MMP/TIMP ratio may be involved in the elevated IOP often associated with glaucoma. The prostaglandin analog/prostamide (PGA) class of topical ocular hypotensive medications used in glaucoma treatment reduces IOP by increasing outflow through both conventional and unconventional (uveoscleral) outflow pathways. Evidence from in vivo and in vitro studies using animal models and anterior segment explant and cell cultures indicates that the mechanism of IOP lowering by PGAs involves increased MMP expression in the TM and ciliary body, leading to tissue remodeling that enhances conventional and unconventional outflow. PGA effects on MMP expression are dependent on the identity and concentration of the PGA. An intracameral sustained-release PGA implant (Bimatoprost SR) in development for glaucoma treatment can reduce IOP for many months after expected intraocular drug bioavailability. We hypothesize that the higher concentrations of bimatoprost achieved in ocular outflow tissues with the implant produce greater MMP upregulation and more extensive, sustained MMP-mediated target tissue remodeling, providing an extended duration of effect.

Cell atlas of aqueous humor outflow pathways in eyes of humans and four model species provides insight into glaucoma pathogenesis

Increased intraocular pressure (IOP) represents a major risk factor for glaucoma, a prevalent eye disease characterized by death of retinal ganglion cells; lowering IOP is the only proven treatment strategy to delay disease progression. The main determinant of IOP is the equilibrium between production and drainage of aqueous humor, with compromised drainage generally viewed as the primary contributor to dangerous IOP elevations. Drainage occurs through two pathways in the anterior segment of the eye called conventional and uveoscleral. To gain insights into the cell types that comprise these pathways, we used high-throughput single-cell RNA sequencing (scRNAseq). From ∼24,000 single-cell transcriptomes, we identified 19 cell types with molecular markers for each and used histological methods to localize each type. We then performed similar analyses on four organisms used for experimental studies of IOP dynamics and glaucoma: cynomolgus macaque (Macaca fascicularis), rhesus macaque (Macaca mulatta), pig (Sus scrofa), and mouse (Mus musculus). Many human cell types had counterparts in these models, but differences in cell types and gene expression were evident. Finally, we identified the cell types that express genes implicated in glaucoma in all five species. Together, our results provide foundations for investigating the pathogenesis of glaucoma and for using model systems to assess mechanisms and potential interventions.

Treatment of vertebrobasilar insufficiency

This article provides an up-to-date literature review on the role of pathological changes in the extracranial, trunk segments of the vertebral arteries (VA) in the development of chronic and progressive vertebrobasilar insufficiency (VBI). Improving methodology of differentiated reconstructive interventions for VA stenosis based on specifically determined vascular territory with application of microsurgery instruments and minimally invasive technologies has made it possible to determine that all other conditions that could lead to the formation of VBI should be excluded in patients with this clinical picture during the planning of arterial reconstruction, and possible outflow pathways and reactivity of the arteries of the vertebrobasilar territory should be determined.

A Novel Non‐Prostaglandin EP2‐Receptor Agonist for Glaucoma Treatment: Omidenepag Isopropyl (DE‐117)

PurposeElevated intraocular pressure (IOP) is often associated with Primary Open‐Angle Glaucoma (POAG), an optic neuropathy that afflicts millions of people and which can cause blindness if left untreated. Omidenepag Isopropyl (OMDI; DE‐117) is a novel pro‐drug non‐prostaglandin (PG) which hydrolyzes to release its active free acid form (Omidenepag; OMD) into the aqueous humor (AQH) after topical ocular (t.o.) instillation. The purpose of the current studies was to characterize OMDI and OMD in several in vitro and in vivo model systems in order to determine its IOP‐lowering and other pharmacological properties.MethodsWell‐accepted in vitro cell‐based assays and in vivo IOP measurement techniques were utilized in the current studies.ResultsOMD was found to be a highly selective EP2 receptor (EP2R) agonist that bound to the EP2R with a high affinity (Ki = 3.6 nM) and which potently increased intracellular cAMP (EC50 = 8.3 nM). Once daily (q.d.), single t.o. dosing with OMDI (0.0001–0.01%) potently and efficaciously lowered IOP in ocular normotensive rabbits, dogs and monkeys, and also in ocular hypertensive (OHT) monkeys. Repeated t.o. dosing with OMDI in dogs did not cause tachyphylaxis of IOP reduction.Additive IOP‐lowering to OMDI was observed with Timolol, Brimonidine and Brinzolamide in rabbits and monkeys. OMDI 0.002% t.o. lowered IOP by increasing AQH efflux via trabecular meshwork (TM) and uveoscleral (UVSC) outflow pathways in OHT monkey eyes. In a phase‐3 clinical study, 0.002% OMDI (q.d.; t.o.), an optimal dose, lowered IOP by 5–7 mmHg in OHT/POAG patients (baseline IOPs of 22–34 mmHg) that was maintained over 12‐months with equivalent efficacy to Xalatan (0.005%, q.d.; t.o.). OHT/POAG patients that were low‐ or non‐responders to Xalatan (0.005%, q.d.; t.o.) exhibited significant IOP‐lowering (additional 3 mmHg) when switched to OMDI 0.002% (q.d.; t.o.). OMDI was well tolerated and produced transient conjunctival hyperemia, and mild iritis and macular edema (ME) in a few patients. However, no iris color changes, DUES, or abnormal eyelash growth were noted after 12‐month q.d. t.o. dosing with 0.002% OMDI, unlike FP‐receptor PG agonists (Bimatoprost and Latanoprost). Additive IOP‐lowering was also observed in OHT/POAG patients when OMDI (0.002%; q.d.) and Timolol (a known ocular hypotensive beta‐antagonist; 0.05%, b.i.d.) were t.o. instilled.ConclusionIn conclusion, the non‐prostaglandin organic molecule, OMD, is a highly selective and potent EP2R agonist whose isopropyl ester (OMDI) was shown to be a potent and efficacious ocular hypotensive agent in several animal species and in the OHT/POAG patient population studied. OMDI promoted AQH outflow via both the TM and UVSC pathways to lower IOP, and it achieved a comparable ocular hypotensive efficacy to Latanoprost (Xalatan 0.005% q.d.; t.o.). Additional IOP reduction was observed in Xalatan‐non/low responders when switched over to 0.002% OMDI. Additive IOP‐lowering efficacy was also observed when OMDI was t.o. dosed along with other ocular hypotensive drugs. These pharmacological and clinical efficacy features of OMDI support further development of this drug candidate for treating OHT and glaucoma.

The β4-Subunit of the Large-Conductance Potassium Ion Channel KCa1.1 Regulates Outflow Facility in Mice.

PurposeThe large-conductance calcium-activated potassium channel KCa1.1 (BKCa, maxi-K) influences aqueous humor outflow facility, but the contribution of auxiliary β-subunits to KCa1.1 activity in the outflow pathway is unknown.MethodsUsing quantitative polymerase chain reaction, we measured expression of β-subunit genes in anterior segments of C57BL/6J mice (Kcnmb1-4) and in cultured human trabecular meshwork (TM) and Schlemm's canal (SC) cells (KCNMB1-4). We also measured expression of Kcnma1/KCNMA1 that encodes the pore-forming α-subunit. Using confocal immunofluorescence, we visualized the distribution of β4 in the conventional outflow pathway of mice. Using iPerfusion, we measured outflow facility in enucleated mouse eyes in response to 100 or 500 nM iberiotoxin (IbTX; N = 9) or 100 nM martentoxin (MarTX; N = 12). MarTX selectively blocks β4-containing KCa1.1 channels, whereas IbTX blocks KCa1.1 channels that lack β4.Results Kcnmb4 was the most highly expressed β-subunit in mouse conventional outflow tissues, expressed at a level comparable to Kcnma1. β4 was present within the juxtacanalicular TM, appearing to label cellular processes connecting to SC cells. Accordingly, KCNMB4 was the most highly expressed β-subunit in human TM cells, and the sole β-subunit in human SC cells. To dissect functional contribution, MarTX decreased outflow facility by 35% (27%, 42%; mean, 95% confidence interval) relative to vehicle-treated contralateral eyes, whereas IbTX reduced outflow facility by 16% (6%, 25%).ConclusionsThe β4-subunit regulates KCa1.1 activity in the conventional outflow pathway, significantly influencing outflow function. Targeting β4-containing KCa1.1 channels may be a promising approach to lower intraocular pressure to treat glaucoma.

Transcriptome‐wide study of the response of human trabecular meshwork cells to the substrate stiffness increase

Elevated intraocular pressure, a major risk factor of glaucoma, is caused by the abnormal function of trabecular outflow pathways. Human trabecular meshwork (HTM) tissue plays an important role in the outflow pathways. However, the molecular mechanisms that how TM cells respond to the elevated IOP are largely unknown. We cultured primary HTM cells on polyacrylamide gels with tunable stiffness corresponding to Young's moduli ranging from 1.1 to 50 kPa. Then next-generation RNA sequencing (RNA-seq) was performed to obtain the transcriptomic profiles of HTM cells. Bioinformatics analysis revealed that genes related to glaucoma including DCN, SPARC, and CTGF, were significantly increased with elevated substrate stiffness, as well as the global alteration of HTM transcriptome. Extracellular matrix (ECM)-related genes were selectively activated in response to the elevated substrate stiffness, consistent with the known molecular alteration in glaucoma. Human normal and glaucomatous TM tissues were also obtained to perform RNA-seq experiments and supported the substrate stiffness-altered transcriptome profiles from the in vitro cell model. The current study profiled the transcriptomic changes in human TM cells upon increasing substrate stiffness. Global change of ECM-related genes indicates that the in vitro substrate stiffness could greatly affect the biological processes of HTM cells. The in vitro HTM cell model could efficiently capture the main pathogenetic process in glaucoma patients, and provide a powerful method to investigate the underlying molecular mechanisms.

Identification and activity of the functional complex between hnRNPL and the pseudoexfoliation syndrome-associated lncRNA, LOXL1-AS1.

Individuals with pseudoexfoliation (PEX) syndrome exhibit various connective tissue pathologies associated with dysregulated extracellular matrix homeostasis. PEX glaucoma is a common, aggressive form of open-angle glaucoma resulting from the deposition of fibrillary material in the conventional outflow pathway. However, the molecular mechanisms that drive pathogenesis and genetic risk remain poorly understood. PEX glaucoma-associated single-nucleotide polymorphisms are located in and affect activity of the promoter of LOXL1-AS1, a long non-coding RNA (lncRNA). Nuclear and non-nuclear lncRNAs regulate a host of biological processes, and when dysregulated, contribute to disease. Here we report that LOXL1-AS1 localizes to the nucleus where it selectively binds to the mRNA processing protein, heterogeneous nuclear ribonucleoprotein-L (hnRNPL). Both components of this complex are critical for the regulation of global gene expression in ocular cells, making LOXL1-AS1 a prime target for investigation in PEX syndrome and glaucoma.

Circumferential canal surgery: a brief history.

Purpose of reviewMost microinvasive glaucoma surgery (MIGS) procedures bypass outflow resistance residing proximally in the trabecular meshwork and inner wall of Schlemm's canal. A novel procedure combining trabeculotomy with viscodilation adds to this by also addressing distal resistance of the canal and collector channel ostia. This review examines the development and evidence for both trabeculotomy and canaloplasty separately and the combination in a single procedure.Recent findingsRecent aqueous angiography studies have confirmed the segmental nature of outflow through Schlemm's canal highlighting the need to address distal outflow pathway resistance. Combined trabeculotomy and viscodilation ab interno is a novel approach with a new purpose-designed device (OMNI Surgical System) becoming available to surgeons in early 2018. Recent results as both a standalone and combined with cataract procedure demonstrate significant intraocular pressure reductions with an average 41% reduction from baseline in the pseudophakic group.SummaryTargeting both distal as well as proximal points of outflow resistance in the conventional pathway may prove to be a highly efficacious MIGS modality. Additional large prospective studies are currently ongoing to confirm these preliminary results.

A bioengineering approach to Schlemm's canal-like stem cell differentiation for in vitro glaucoma drug screening

Human Schlemm's canal (HSC) cells are critical for understanding outflow physiology and glaucoma etiology. However, primary donor cells frequently used in research are difficult to isolate. HSC cells exhibit both vascular and lymphatic markers. Human adipose-derived stem cells (ADSCs) represent a potential source of HSC due to their capacity to differentiate into both vascular and lymphatic endothelial cells, via VEGF-A and VEGF-C. Shear stress plays a critical role in maintaining HSC integrity, function, and PROX1 expression. Additionally, the human trabecular meshwork (HTM) microenvironment could provide cues for HSC-like differentiation. We hypothesize that subjecting ADSCs to VEGF-A or VEGF-C, shear stress, and co-culture with HTM cells could provide biological, mechanical, and cellular cues necessary for HSC-like differentiation. To test this hypothesis, effects of VEGF-A, VEGF-C, and shear stress on ADSC differentiation were examined and compared to primary HSC cells in terms of cell morphology, and HSC marker expression using qPCR, immunoblotting, and immunocytochemistry analysis. Furthermore, the effect of co-culture with HTM cells on porous scaffolds on ADSC differentiation was studied. Treatment with VEGF-C under shear stress is effective in differentiating ADSCs into PROX1-expressing HSC-like cells. Co-culture with HTM cells on porous scaffolds leads to HTM/ADSC-derived HSC-like constructs that regulate through-flow and respond as expected to dexamethasone. Statement of significanceWe successfully generated human Schlemm's canal (HSC) like cells from adipocyte-derived stem cells induced by biochemical and biomechanical cues as well as bioengineered human trabecular meshwork (HTM) on micropatterned, porous SU8 scaffolds. These stem cell-derived HSC-like cells co-cultured with HTM cells on SU8 scaffolds can regulate through-flow, and in particular, are responsive to steroid treatment as expected. These findings show that ADSC-derived HSC-like cells have the potential to recreate the ocular outflow pathway for in vitro glaucoma drug screening.To the best of our knowledge, it is the very first time to demonstrate derivation of Schlemm's canal-like cells from stem cells. It provides an important alternative source to primary Schlemm's canal cells that are very difficult to be isolated and cultured from human donors.

Sustained Nitric Oxide-Providing Small Molecule and Precise Release Behavior Study for Glaucoma Treatment.

Incidence ofglaucoma, a severe disease leading to irreversible loss of vision, is increasing with global aging populations. Lowering intraocular pressure (IOP) is the only proven treatment method for glaucoma. Nitric oxide (NO) is an emerging material targeting the conventional outflow pathway by relaxing the trabecular meshwork (TM). However, there is little understanding on the NO level effective in IOP lowering without toxicity. Here, we report a novel long-term NO-releasing polydiazeniumdiolate (NOP) that enables lowering IOP via the conventional outflow pathway. NOP is composed of carbon-bound polydiazeniumdiolate, a stable NO donor moiety. NO release was monitored with accurate parameters by real-time detection of gas and analysis of the accumulated release profile. Based on the NO release information, the selected safe level of NOP exhibited effective TM relaxation and a potential IOP lowering effect in vivo without side effects. This work provides new insights into nitric oxide release behavior that should be considered for glaucoma treatment.

Анализ состояния внутриглазного давления после факоэмульсификации с имплантацией ИОЛ при сочетании катаракты с первичной открытоугольной глаукомой

Purpose. To evaluate the effectiveness of surgical resection of the sclera in patients with primary open-angle and secondary glaucoma. Materials and methods. The study included 84 patients with POAG and SG stages III-IV and decompensated IOP level (not higher than 32 mm Hg). In order to normalize the increased ophthalmotonus, a non - penetrating operation was performed-surgical resection of the sclera (SRS). The patients underwent complex ophthalmological examination and dynamic observation. Result. In the studied groups of patients after surgical treatment there was a decrease in elevated IOP levels by 33.42%, an improvement in the coefficient of ease of outflow and a weakening of the hypotensive regime. Stabilization of visual functions was observed in all patients. Summary. The proposed new SRS technique provides a smooth decrease in IOP, preservation of visual functions and is not accompanied by intra-and postoperative complications. Key words: primary open-angle glaucoma, surgical resection of sclera, secondary glaucoma, uveoscleral outflow pathway (USPO), intraocular pressure, EO coefficient .

Хирургическая резекция склеры – непроникающая операция для лечения больных с первичной открытоугольной и вторичной глаукомой

Purpose. To evaluate the effectiveness of surgical resection of the sclera in patients with primary open-angle and secondary glaucoma. Materials and methods. The study included 84 patients with POAG and SG stages III-IV and decompensated IOP level (not higher than 32 mm Hg). In order to normalize the increased ophthalmotonus, a non - penetrating operation was performed-surgical resection of the sclera (SRS). The patients underwent complex ophthalmological examination and dynamic observation. Result. In the studied groups of patients after surgical treatment there was a decrease in elevated IOP levels by 33.42%, an improvement in the coefficient of ease of outflow and a weakening of the hypotensive regime. Stabilization of visual functions was observed in all patients. Summary. The proposed new SRS technique provides a smooth decrease in IOP, preservation of visual functions and is not accompanied by intra-and postoperative complications. Key words: primary open-angle glaucoma, surgical resection of sclera, secondary glaucoma, uveoscleral outflow pathway (USPO), intraocular pressure, EO coefficient .

Experimental glaucoma model with controllable intraocular pressure history

Glaucoma-like neuropathies can be experimentally induced by disturbing aqueous outflow from the eye, resulting in intraocular pressure (IOP) changes that are variable in magnitude and time course and permanent in duration. This study introduces a novel method of glaucoma induction that offers researchers round-the-clock measurement and reversible control of IOP for the first time. One eye of Brown-Norway rats was implanted with a cannula tethered to a pressure sensor and aqueous reservoir. IOP was raised 10 mmHg for weeks-to-months in treated animals and unaltered in control animals. Counts of Brn3a-expressing retinal ganglion cells (RGCs) in implanted eyes were indistinguishable from non-implanted eyes in control animals and 15 ± 2%, 23 ± 4%, and 38 ± 4% lower in animals exposed to 2, 4, and 9 weeks of IOP elevation. RGC loss was greater in peripheral retina at 2 weeks and widespread at longer durations. Optic nerves also showed progressive degeneration with exposure duration, yet conventional outflow facility of implanted eyes was normal (24.1 ± 2.9 nl/min/mmHg) even after 9-weeks elevation. Hence, this infusion-based glaucoma model exhibits graded neural damage with unimpaired outflow pathways. The model further revealed a potentially-significant finding that outflow properties of rat eyes do not remodel in response to chronic ocular hypertension.

СОСТОЯНИЕ ОБОЛОЧЕК ЗРИТЕЛЬНЫХ НЕРВОВ И ПУТИ ОТТОКА КРОВИ ИЗ ПОЛОСТИ ЧЕРЕПА В 21-СУТОЧНОЙ «СУХОЙ» ИММЕРСИИ ПО ДАННЫМ УЛЬТРАЗВУКОВЫХ МЕТОДОВ ИССЛЕДОВАНИЯ

Venous blood circulation and liquid dynamics in the brain, and collateral venous blood circulation were investigated in participants of 21-day dry immersion study. The ultrasonic technique was used to measure the optic nerve sheaths, register hemodynamics in the internal jugular vein, inferior vena cava and superficial femoral vein. We observed a significant acceleration of blood flow through the jugular veins by day 7 with a decrease in the lumen of the jugular veins and a gradual expansion of the liquor space around the optic nerves. Hemodynamics in the vena cava inferior as a potential collateral of outflow from the cranial cavity indirectly suggests reorganization of the outflow pathway and venous blood distribution between the jugular and vertebral pathways in specific periods of exposure to immersion. After the immersion, all hemodynamic parameters returned to their initial levels; however, after two weeks of recovery the inverse trend in the state of optic nerve sheaths was observed only in some of the participants.

Endovascular revascularisation in patients with necrotic wounds and extended infrainguinal arterial disease

To report own experience of endovascular interventions in patients with extended occlusive lesion (TASC II D) of the femoral-popliteal and tibial arteries and concomitant purulent-necrotic wounds. We have analyzed literature data and own experience of endovascular interventions in patients with extended occlusive lesion (TASC II D) of the femoral-popliteal and tibial arteries and concomitant purulent-necrotic wounds. Endovascular strategy is preferable in a certain subgroup of patients with extended infrainguinal lesions. Considering own data, we assumed the need for routine correction of outflow pathways (simultaneous angioplasty of at least 2 tibial arteries). Primary results are encouraging, but further research is required.

<p>Canaloplasty in the Treatment of Primary Open-Angle Glaucoma: Patient Selection and Perspectives</p>

Canaloplasty is a surgical procedure that has undergone a number of developments since its introduction in 2005. Many thousands of canaloplasties have been performed around the world since then and is, by definition, a blebless procedure. It does not necessitate the use of any antifibrotic agents and results in safe and effective IOP reductions in patients with open-angle glaucoma (OAG) with minimal complications and no bleb-related adverse events. When considering the surgical management of patients with early and medium stages of the disease, canaloplasty can be considered as a first line option. This paper will overview the theoretical effectiveness of canal surgery, the fundamental aspects of aqueous outflow resistance with particular emphasis on the role of the trabecular meshwork, Schlemm’s canal, and the collector channels, and the methods available for the clinical evaluation of the outflow pathways in relation to the ocular anatomy. Further, the paper will detail the surgical technique itself and how this has developed over time together with the clinical aspects that should be accounted for when selecting patients for this surgery.

Computational modelling of fluid and solute transport in the brain.

The glymphatic system is proposed to be a unidirectional fluid and solute circulation pathway in the brain involving transport through perivascular spaces, brain interstitium and glial cells. Some aspects of the glymphatic hypothesis are controversial, particularly the outflow pathway, and little is known about the forces that govern such fluid transport at each stage. Computational and mathematical modelling approaches can be valuable for testing hypotheses and are a useful adjunct to experimental research in this field. This article presents an overview of computational modelling studies associated with glymphatic fluid transport in the brain, from fluid inflow, transparenchymal transport and outflow. A broad range of modelling approaches have been used to investigate fluid and solute transport from purely analytical models to hydraulic resistance networks and computational fluid dynamics models. Most of the modelling attention has focused on periarterial inflow and transport through the parenchyma. Collectively these studies suggest that arterial pulsation is unlikely to be the sole inflow driving force, and diffusion is most likely the dominant mode of transport in the parenchymal extracellular spaces. Models of efflux are limited and have not been able to shed light on the driving forces for fluid outflow from the central nervous system.

Efficacy of Needling Revision After XEN Gel Stent Implantation: A Prospective Study

The XEN gel stent is currently the only minimally invasive glaucoma surgical device that targets the subconjunctival outflow pathway through an ab interno placement. It has demonstrated a significant intraocular pressure (IOP)-lowering potential and a favorable safety profile compared with traditional filtering surgery. However, despite a less invasive approach, the presence of a filtering bleb inevitably implies some risk of complications. The most commonly reported bleb-related complication, with rates as high as 45%, is bleb fibrosis associated with raised IOP. To restore filtration in those failing blebs, needling revision is considered the procedure of choice. In this study, we present the results of mitomycin C-augmented needling after XEN implantation. This was a prospective, interventional study, conducted at a single tertiary glaucoma center. Fifty-one eyes of 51 patients with raised IOP associated with either a fibrotic or shallow bleb or increased vascularity following XEN gel stent implantation at the investigation site between January 2015 and June 2016 were enrolled in this study. Patients with other identified causes of filtration failure (stent malposition, internal ostium obstruction, retained viscoelastic) were excluded. Included patients who underwent mitomycin C-augmented needling revision, and follow-up examinations were conducted at 1 day, 1 week, and 1, 3, 6, 12, 18, and 24 months. The primary outcome was the magnitude of IOP reduction following needling revision at the last follow-up visit. Secondary outcome measures were the number of needling procedures carried out in all patients, the rate of patients requiring further filtering surgery following needling revision, and the rate of intraoperative and postoperative complications associated with needling revisions. The average age was 74.4±9.6 years; 66.7% (n=34) were female individuals. Primary open-angle glaucoma was the most common diagnosis (n=21, 41.2%). A total of 78 needling procedures were performed over the 24-month follow-up. Overall 20 of 51 eyes (39.2%) required >1 needling revision, and 14 eyes (24.5%) eventually required reoperation to maintain IOP within their desired target range. Before XEN implantation, mean preoperative IOP was 22.3±8.2 mm Hg and decreased to 14.1±8.0 mm Hg at day 1 postoperatively (-36.8%). The last measured IOP before the first needling revision was on average 23.6±8.9 mm Hg, which reduced to a mean 12.1±4.2 mm Hg at the first postrevision appointment (-48.7%). At the last follow-up appointment, on average 17.0±7.0 months after the first needling, the mean IOP was 14.3±4.1 mm Hg (-35.9% and -39.4% from preoperative and prerevision baselines, respectively). Complications associated with needling revisions were partial amputation of the XEN implant during needling (n=2, 3.9%), hypotony with choroidal detachment (n=1, 2%), and failure to achieve target IOP requiring subsequent surgery (n=14, 27.5%). No association was found between any of the recorded characteristics and the number of needling revisions performed or their outcomes. The present study shows that needling revision following XEN gel stent implantation is a relatively safe and efficient intervention to restore filtration in failing blebs, with a significant and durable IOP-reduction potential.

Progression on canaloplasty for primary open angle glaucoma.

As a non-penetrating glaucoma surgery (NPGS), canaloplasty aims to reconstruct the physiological outflow of aqueous humor by dilating the Schlemm's canal. Ab interno canaloplasty (ABiC), which can reconstruct the natural outflow pathways of aqueous humor in mild-to-moderate primary open angle glaucoma (POAG) patients, is a new minimally invasive glaucoma surgery (MIGS) procedure improving from traditional canaloplasty. Canaloplasty can reduce intraocular pressure (IOP) with high efficiency and security. There are no complications such as scar formation and encapsulation for this no-bleb canaloplasty.

Targeting the vascular-specific phosphatase PTPRB protects against retinal ganglion cell loss in a pre-clinical model of glaucoma.

Elevated intraocular pressure (IOP) due to insufficient aqueous humor outflow through the trabecular meshwork and Schlemm's canal (SC) is the most important risk factor for glaucoma, a leading cause of blindness worldwide. We previously reported loss of function mutations in the receptor tyrosine kinase TEK or its ligand ANGPT1 cause primary congenital glaucoma in humans and mice due to failure of SC development. Here, we describe a novel approach to enhance canal formation in these animals by deleting a single allele of the gene encoding the phosphatase PTPRB during development. Compared to Tek haploinsufficient mice, which exhibit elevated IOP and loss of retinal ganglion cells, Tek+/-;Ptprb+/- mice have elevated TEK phosphorylation, which allows normal SC development and prevents ocular hypertension and RGC loss. These studies provide evidence that PTPRB is an important regulator of TEK signaling in the aqueous humor outflow pathway and identify a new therapeutic target for treatment of glaucoma.