Engineered sensor actuator modulator as aqueous humor outflow actuator for gene therapy of primary open-angle glaucoma.

Glaucoma, a blinding eye disease with optic neuropathy, is usually associated with elevated intraocular pressure (IOP). The currently available pharmacological and surgical treatments for glaucoma have significant limitations and side effects, which include systemic reactions to medications, patient non-compliance, eye infections, surgical device failure, and damage to the eye. Here, we present Sensor-Actuator-Modulator (SAM), an engineered double mutant version of the bacterial stretch-activated mechanosensitive channel of large conductance (MscL) that directly senses tension in the membrane lipid bilayer of cells and in response, transiently opens its large nonspecific pore to release cytoplasmic fluid. The heterologously expressed mechanosensitive SAM channel acts as a tension-activated pressure release valve in trabeculocytes. In the trabecular meshwork (TM), SAM is activated by membrane stretch caused by elevated IOP. We have identified several SAM variants that are activated at physiologically relevant pressures. Using this barogenetic technology, we have demonstrated that SAM is functional in cultured TM cells, and successfully transduced in vivo in TM cells by use of AAV2/8. Further, it is effective in enhancing aqueous humor outflow facility leading to lowering the IOP in a mouse model of ocular hypertension.

Autoregulation of intraocular pressure via expression of a mechanosensitive channel of large conductance in trabecular meshwork serves as a mutation-agnostic gene therapy for glaucoma.

Systemic Diseases in Primary Open-Angle Glaucoma. / Internistische Erkrankungen und Zusammenhang mit dem primären Offenwinkelglaukom.

Primary open-angle glaucoma is a neurodegenerative disease with progressive chronic optic neuropathy and corresponding visual field defects. In this literature review, we discuss systemic diseases and their mechanism for developing glaucoma, including systemic hypertension and hypotension, diabetes, dyslipidemia, obstructive sleep apnoea syndrome, chronic kidney disease, migraine, and polypharmacy.

[Standardizing the diagnosis and treatment of ocular hypertension based on evidence-based medicine].

Ocular hypertension (OHT) refers to a condition in which the intraocular pressure increases without causing glaucomatous optic nerve changes or visual field damage. The incidence rate of OHT in people over 40 years old is as high as 4% to 10%. According to the OHT Treatment Study (OHTS), the incidence of primary open angle glaucoma (POAG) among OHT patients is increasing year by year, so it is necessary to conduct long-term follow-up. This article elaborates on five major risk factors for the progression of OHT to POAG: age, intraocular pressure, vertical cup-disc ratio, pattern standard deviation of visual field, and central corneal thickness. It also summarizes other potential risk factors, such as long-term fluctuations in intraocular pressure, asymmetry of intraocular pressure and visual field between the two eyes, structural phenotypes of the optic disk, and optic disk hemorrhage. Predicting the risk of OHT progression to POAG based on risk factors, patients with different risk levels require different timing for treatment initiation and follow-up intervals. Those with higher risks should start preventive treatment earlier and have shorter follow-up intervals. Both drug therapy and selective laser trabeculoplasty can serve as initial treatment options for OHT. Combining evidence-based medicine research and individualized evaluation of treatment can enhance the clinical diagnosis and treatment level of OHT.

iPSCs-Based Therapy for Trabecular Meshwork.

The trabecular meshwork (TM) of the eye serves as an essential tissue in controlling aqueous humor (AH) outflow and intraocular pressure (IOP) homeostasis. However, dysfunctional TM cells and/or decreased TM cellularity is become a critical pathogenic cause for primary open-angle glaucoma (POAG). Consequently, it is particularly valuable to investigate TM characteristics, which, in turn, facilitates the development of new treatments for POAG. Since 2006, the advancement in induced pluripotent stem cells (iPSCs) provides a new tool to (1) model the TM in vitro and (2) regenerate degenerative TM in POAG. In this context, we first summarize the current approaches to induce the differentiation of TM-like cells from iPSCs and compare iPSC-derived TM models to the conventional in vitro TM models. The efficacy of iPSC-derived TM cells for TM regeneration in POAG models is also discussed. Through these approaches, iPSCs are becoming essential tools in glaucoma modeling and for developing personalized treatments for TM regeneration.

Glaucoma: Diagnosis and Management.

Glaucoma is a group of eye disorders characterized by progressive deterioration of the optic nerve that can lead to vision loss. Primary open-angle glaucoma (POAG) is the most common form in the United States. The risk of POAG increases with age, family history of glaucoma, type 2 diabetes mellitus, hypotension, hypothyroidism, obstructive sleep apnea, cardiovascular disease, and myopia. Up to one-half of patients are undiagnosed because a diagnosis often requires monitoring over years to document changes suggesting POAG. These include a cup-to-disc ratio of 0.3 or greater, intraocular pressure greater than 21 mm Hg on tonometry, nerve fiber layer defects identified on optical coherence tomography, and reproducible visual field defects. Topical intraocular pressure-lowering medications and selective laser trabeculoplasty are first-line treatments for POAG. Although POAG screening in the general adult population is not recommended, primary care physicians can help decrease POAG-related vision loss by identifying patients with risk factors and referring them for evaluation by an eye specialist. Medicare covers evaluations in patients at high risk. Primary care physicians should encourage medication adherence and identify barriers to treatment. The other type of glaucoma is angle-closure glaucoma, in which the flow of aqueous humor is obstructed. Angle-closure glaucoma can occur acutely with pupillary dilation and is an ophthalmologic emergency. The goal of treatment for acute angle-closure glaucoma is to reduce intraocular pressure quickly with medications or surgery, then prevent the recurrence of the obstruction to aqueous flow by a definitive ophthalmologic procedure.

Effect of alternate nostril breathing exercise on autonomic functions, ocular hypertension, and quality of life in elderly with systemic hypertension and high-tension primary open-angle glaucoma.

Investigating the response of ocular hypertension and quality of life to a 4-week alternate-nostril breathing exercise (ANBE) in older adults with systemic hypertension (SH) and high-tension form of primary open-angle glaucoma (HTF-POAG) was our aim. Sixty older adults with SH and HTF-POAG were randomly assigned to the ANBE group (n=30, received morning and evening 30 min sessions of daily ANBE) or the control (waitlist) group (n=30). Right-eye intraocular pressure (IOP), left-eye IOP, blood pressure, short-form-36 survey (SF36S), rates of respiration and radial-artery pulsation, hospital anxiety and depression scale (depression subscale abbreviated as HADS-D and anxiety subscale abbreviated as HADS-A), and glaucoma quality-of-life 15-item questionnaire (GQoL-15) were assessed. All measurements were improved in the ANBE group only. In conclusion, a 4-week ANBE could be an adjunctive modality to improve HADS-D, rates of respiration and radial-artery pulsation, HADS-A, blood pressure, IOP, GQol-15, and SF36S in older adults SH and HTF-POAG.

Chronic Open Angle Glaucoma: a Biopsychosocial Approach to Patient Care.

It is estimated that 2.2 billion people are affected by impaired vision resulting from eye conditions. Chronic open angle glaucoma (COAG) is one such condition, which primarily affects older adults, and is linked to other factors such as genetic predisposition, high blood pressure, diabetes and smoking. By 2025, it is projected that 44% of the UK's ageing population will have COAG. Vision loss due to this condition is irreversible. In this article, Penelope Stanford discusses the bioscience of COAG, and provides information on access to care and patient interventions.

Comparative Cost-effectiveness of Trabeculectomy versus MicroShunt in the US Medicare System.

PURPOSE: To assess the societal cost-utility of the MicroShunt compared with trabeculectomy for the surgical management of glaucoma in the US Medicare system. DESIGN: Cost-utility analysis using efficacy and safety results of a randomized controlled trial and other pivotal clinical trials. PARTICIPANTS: Markov model cohort of patients with open-angle glaucoma. METHODS: Open-angle glaucoma treatment costs and effects were analyzed with a deterministic model over a 1-year horizon using TreeAge software. Health states included the Hodapp-Parrish-Anderson glaucoma stages (mild, moderate, advanced, blind) and death. Both treatment arms received additional ocular hypotensive agents to control intraocular pressure (IOP). Treatment effect was measured as mean number of ocular hypotensive medications and reduction in IOP, which had a direct impact on transition probabilities between health states. Analyses of scenarios were performed with longer time horizons. One-way sensitivity and probabilistic sensitivity analyses were conducted to assess the impact of alternative model inputs. Both treatment arms were subject to reported complication rates, which were factored in the model. MAIN OUTCOME MEASURES: Incremental cost per quality-adjusted life-year (QALY) gained. RESULTS: At 1 year, the MicroShunt had an expected cost of US dollars (USD) 6318 compared with USD 4260 for trabeculectomy. MicroShunt patients gained 0.85 QALYs compared with 0.86 QALYs for trabeculectomy, resulting in a dominated incremental cost-utility ratio of USD 187 680. Dominance is a health economic term used to describe a treatment option that is both more costly and less effective than the alternative. The MicroShunt remained dominant in 1-way sensitivity analyses using best-case input parameters (including a device fee of USD 0). At a willingness-to-pay threshold of USD 50 000, the likelihood of the MicroShunt being cost-effective was 6.4%. Dominance continued in longer time horizons, up to 20 years. CONCLUSIONS: Trabeculectomy appears to be a dominant treatment strategy over the MicroShunt in the surgical management of glaucoma. More independent, long-term studies are required for the MicroShunt and other subconjunctival microstent devices to evaluate their use in clinical practice.

Juvenile open angle glaucoma: current diagnosis and management.

PURPOSE OF REVIEW: The aim of this article is to summarize up-to-date research on the diagnosis and management of juvenile open-angle glaucoma (JOAG). RECENT FINDINGS: JOAG can be subclassified into four clinical phenotypes, and faster myopic shift is a risk factor for disease progression. Vessel density is associated with structural damage and worsening visual acuity in JOAG and can be monitored with optical coherence tomography angiography. Genetic studies have revealed molecular causes of JOAG including variants in CPAMD8, MYOC, and CYP1B1. Tube shunt surgeries as well as gonioscopy-assisted transluminal trabeculotomy have been shown to be successful in JOAG. SUMMARY: Although genetic advances may improve future screening, intraocular pressure monitoring and fundoscopic exam remain the current mainstay of diagnosis. Medical treatment alone for JOAG is typically insufficient with patients requiring surgical management. Selective laser trabeculoplasty may delay or decrease the need for surgery. Trabeculectomy has traditionally been shown to be effective in JOAG, but tube shunt surgery and microinvasive glaucoma surgery are effective alternatives.

TET-dependent GDF7 hypomethylation impairs aqueous humor outflow and serves as a potential therapeutic target in glaucoma.

Glaucoma is the leading cause of irreversible vision loss, affecting more than 70 million individuals worldwide. Circulatory disturbances of aqueous humor (AH) have long been central pathological contributors to glaucomatous lesions. Thus, targeting the AH outflow is a promising approach to treat glaucoma. However, the epigenetic mechanisms initiating AH outflow disorders and the targeted treatments remain to be developed. Studying glaucoma patients, we identified GDF7 (growth differentiation factor 7) hypomethylation as a crucial event in the onset of AH outflow disorders. Regarding the underlying mechanism, the hypomethylated GDF7 promoter was responsible for the increased GDF7 production and secretion in primary open-angle glaucoma (POAG). Excessive GDF7 protein promoted trabecular meshwork (TM) fibrosis through bone morphogenetic protein receptor type 2 (BMPR2)/Smad signaling and upregulated pro-fibrotic genes, α-smooth muscle actin (α-SMA) and fibronectin (FN). GDF7 protein expression formed a positive feedback loop in glaucomatous TM (GTM). This positive feedback loop was dependent on the activated TET (ten-eleven translocation) enzyme, which kept the GDF7 promoter region hypomethylated. The phenotypic transition in TM fortified the AH outflow resistance, thus elevating the intraocular pressure (IOP) and attenuating the nerve fiber layer. This methylation-dependent mechanism is also confirmed by a machine-learning model in silico with a specificity of 84.38% and a sensitivity of 89.38%. In rhesus monkeys, we developed GDF7 neutralization therapy to inhibit TM fibrosis and consequent AH outflow resistance that contributes to glaucoma. The neutralization therapy achieved high-efficiency control of the IOP (from 21.3 ± 0.3 to 17.6 ± 0.2 mmHg), a three-fold improvement in the outflow facility (from 0.1 to 0.3 µL/min · mmHg), and protection of nerve fibers. This study provides new insights into the epigenetic mechanism of glaucoma and proposes an innovative GDF7 neutralization therapy as a promising intervention.

Screening for Primary Open-Angle Glaucoma: US Preventive Services Task Force Recommendation Statement.

Importance: Glaucoma affects an estimated 2.7 million people in the US. It is the second-leading cause of irreversible blindness in the US and the leading cause of blindness in Black and Hispanic/Latino persons. Objective: To update its 2013 recommendation, the US Preventive Services Task Force (USPSTF) commissioned a systematic review to evaluate the benefits and harms of screening for glaucoma in adults. Population: Adults 40 years or older who present in primary care and do not have signs or symptoms of open-angle glaucoma. Evidence Assessment: The USPSTF concludes that the evidence is insufficient to assess the balance of benefits and harms of screening for glaucoma in adults. The benefits and harms of screening for glaucoma in adults are uncertain. More research is needed. Recommendation: The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for primary open-angle glaucoma in adults. (I statement).

A Review of Neovascular Glaucoma: Etiology, Pathogenesis, Diagnosis, and Treatment.

Neovascular glaucoma (NVG) is a rare, aggressive, blinding secondary glaucoma, which is characterized by neovascularization of the anterior segment of the eye and leading to elevation of the intraocular pressure (IOP). The main etiological factor is retinal ischemia leading to an impaired homeostatic balance between the angiogenic and antiangiogenic factors. High concentrations of vasogenic substances such as vascular endothelial growth factor (VEGF) induce neovascularization of the iris (NVI) and neovascularization of the angle (NVA) that limits the outflow of aqueous humor from the anterior chamber and increases the IOP. NVG clinical, if untreated, progresses from secondary open-angle glaucoma to angle-closure glaucoma, leading to irreversible blindness. It is an urgent ophthalmic condition; early diagnosis and treatment are necessary to preserve vision and prevent eye loss. The management of NVG requires the cooperation of retinal and glaucoma specialists. The treatment of NVG includes both control of the underlying disease and management of IOP. The main goal is the prevention of angle-closure glaucoma by combining panretinal photocoagulation (PRP) and antiangiogenic therapy. The aim of this review is to summarize the current available knowledge about the etiology, pathogenesis, and symptoms of NVG and determine the most effective treatment methods.

Testing the eligibility of glaucoma patients for potential gene therapy among a clinic population.

PURPOSE: Glaucoma patients who deteriorate despite standard treatment may benefit from novel gene therapies. Key inclusion criteria for a glaucoma gene therapy trial were devised. A retrospective chart review in a glaucoma clinic population was conducted. Feasibility of gene therapy inclusion criteria and factors associated with progression and fast progression < -1 decibels/year (dB/y) were evaluated. METHODS: Three hundred and seventy-four primary open-angle glaucoma patients all of whom had performed at least five Swedish interactive threshold algorithm standard visual fields within a 58-month period. Two definitions were applied to characterize visual field progression rate using Guided Progression Analysis for an individual patient based on A, the eye with the greatest visual field loss, or B, the eye with the most rapid progression rate. RESULTS: Mean rate of visual field progression was -0.50 dB/y (Definition A) and -0.64 dB/y (Definition B). 19.0% (A) and 21.9% (B) of eyes, 71 (A) and 82 (B) eyes, were 'fast progressors' (< -1 dB/y). 37 (A) and 43 (B) eyes met the putative gene therapy inclusion criteria (≥ 50 years; mean deviation ≤ -4 to ≥ -12 or ≤ -20 dB, progression rate between -1 and -4 dB/y). Beta blockers (Odds ratio (OR) with 95% Confidence Intervals (CI): 2.84 (1.39-5.80); p = 0.004) (A), (OR (95%CI): 2.48 (1.30-4.75); p = 0.006) (B) and alpha agonists (OR (95%CI): 2.18 (1.14-4.17); p = 0.02) (A), (OR (95%CI) 2.00 (1.08-3.73); p = 0.028) (B) were significantly associated with fast progression. CONCLUSION: A substantial proportion (10%) of patients in this clinic population would meet recommended gene therapy inclusion criteria.

Factors associated with adherence to treatment in patients with open angle glaucoma in Sierra Leone, West Africa: patient demographics and questionnaire.

BACKGROUND: Glaucoma is a significant cause of blindness worldwide. It is more common, presents earlier and is more aggressive in those of African descent. Non-adherence and poor knowledge of glaucoma is a significant barrier to treatment and has been associated with low health literacy. We aim to establish the factors contributing to late presentation, treatment non-adherence and disease progression in glaucoma patients in Sierra Leone. This will help better understand the challenges eye services face, highlight fields requiring development in patient-clinician interaction and identify areas or specific vulnerable patient groups in which resources should be focused. METHODS: Prospective, consecutive recruitment of 120 patients with POAG attending the Lowell and Ruth Gess Eye Hospital and the Connaught Government Teaching Hospital, Freetown, Sierra Leone between February and April 2020. Data were collected from 3 sources: (1) review of clinical notes since first attendance, (2) semi-structured interviews and (3) assessment of study participant's drop instillation technique using a structured checklist. Descriptive statistics was performed for demographic data and other relevant data points. Logistic regression was used for analysis of target variables. RESULTS: The average age was 62 years with more males (52.6%). Agricultural workers and informal street traders represented 13.2% of participants' occupation. 25.8% of participants had no formal school, and 47.4% had either a degree or a diploma. This is out of proportion with the general population and may represent a hidden demographic of glaucoma patients. Drop instillation technique was successful in 52% of study participants. Notable responses to the questionnaire were 30% of patients did not know the name of their eye condition and 22% had no knowledge of glaucoma. CONCLUSION: Investment in a wide-ranging and robust screening programme and public health campaigns targeting these vulnerable groups and high-risk individuals, for example with a positive family history, alongside improved patient education and staff training is required to improve glaucoma care. Support from government, international organisations and the private sector is required to reduce the economic burden of blindness in Sierra Leone.

Two-Year Follow-Up: Therapeutic Success with Respect to Axial Length of Stand-Alone Xen45 Gel Stent Implantation and Combined Procedures.

BACKGROUND: Up to now, no data have been available on the therapeutic success rate of Xen45 gel stent with respect to axial length (AL). The present study aimed to investigate a potential influence of AL on therapeutic success in stand-alone Xen45 gel stent implantation or combination with cataract surgery in open-angle glaucoma patients (OAG) with a follow-up of 2 years. MATERIALS AND METHODS: In this retrospective observational study, 98 eyes of 87 glaucoma patients of the Department of Ophthalmology, University of Erlangen Nürnberg, and from the Erlangen Glaucoma Registry (NCT00494923; ISSN 2191-5008, CS-2011) underwent stand-alone Xen45 gel stent implantation or a combination with cataract surgery. Therapeutic success was defined as ≥ 20% IOP reduction with the same or fewer anti-glaucomatous eye drops needed compared to baseline, yet without additional glaucoma-related surgery (expect bleb needling). Therapeutic failure was classified as any additional glaucoma-related surgery, IOP reduction < 20% or if more local anti-glaucomatous eye drops were applied compared to baseline. RESULTS: The therapeutic success rate was 60.7% (1 year) and 62.5% (2 years). No statistical difference was observed when procedures were combined with cataract surgery (p > 0.05). Subgroup analysis yielded no significantly different therapeutic success when considering glaucoma subtype [1 year: 61.5% (POAG), 60% (SAOG), 2 years: 54.5% (POAG), 69.2% (SOAG); p > 0.05]. Anti-glaucomatous medication use was lowered from 2.72 ± 1.04 at baseline to 0.61 ± 0.99 (1 year) and 0.7 ± 1.04 (2 years). The therapeutic success rate was seen to be independent of axial length for group and subgroup analysis (p > 0.05). Emmetropic eyes (22.0 - 24.5 mm) showed a statistically higher needling rate than myopic eyes (> 24.5 mm, p = 0.02). CONCLUSION: Minimal invasive glaucoma surgery is one therapeutic option in OAG eyes, with good reduction in IOP even after 24 months (with additional bleb needling). Therapeutic success seemed to be independent of axial length in the present study.

[Challenges of long-term glaucoma therapy]. / Problemy dlitel'noi terapii glaukomy.

Primary open-angle glaucoma (POAG) is among the most common causes of irreversible loss of visual functions, its early diagnosis and treatment present great difficulties. POAG development involves many mechanical, hemodynamic and metabolic factors. The main approach to its treatment is reduction and normalization of the intraocular pressure (IOP), starting with local antihypertensive therapy. But since glaucoma requires life-long management, lengthy topical therapy can itself become the cause of many serious issues. Most often, they include achieving consistent normalization of IOP, systemic and local adverse events, difficulties with patient compliance, decreased quality of life, increased risks of the glaucoma surgeries. Ophthalmological practice and research continue to demonstrate the need for changing the paradigm of POAG treatment.

[Classification, diagnosis and treatment of juvenile glaucoma]. / Klassifikatsiya, diagnostika i lechenie yuvenil'noi glaukomy.

Juvenile open-angle glaucoma is a disease with complex pathogenesis affecting young people of working age that can lead to disability. The article describes modern concepts of diagnosis, classification and approaches to the treatment of juvenile glaucoma with special attention paid to the differential diagnostic criteria of juvenile open-angle glaucoma and congenital glaucoma.

Selective laser trabeculoplasty versus eye drops for first-line treatment of ocular hypertension and glaucoma (LiGHT): a multicentre randomised controlled trial.

BACKGROUND: Primary open angle glaucoma and ocular hypertension are habitually treated with eye drops that lower intraocular pressure. Selective laser trabeculoplasty is a safe alternative but is rarely used as first-line treatment. We compared the two. METHODS: In this observer-masked, randomised controlled trial treatment-naive patients with open angle glaucoma or ocular hypertension and no ocular comorbidities were recruited between 2012 and 2014 at six UK hospitals. They were randomly allocated (web-based randomisation) to initial selective laser trabeculoplasty or to eye drops. An objective target intraocular pressure was set according to glaucoma severity. The primary outcome was health-related quality of life (HRQoL) at 3 years (assessed by EQ-5D). Secondary outcomes were cost and cost-effectiveness, disease-specific HRQoL, clinical effectiveness, and safety. Analysis was by intention to treat. This study is registered at controlled-trials.com (ISRCTN32038223). FINDINGS: Of 718 patients enrolled, 356 were randomised to the selective laser trabeculoplasty and 362 to the eye drops group. 652 (91%) returned the primary outcome questionnaire at 36 months. Average EQ-5D score was 0·89 (SD 0·18) in the selective laser trabeculoplasty group versus 0·90 (SD 0·16) in the eye drops group, with no significant difference (difference 0·01, 95% CI -0·01 to 0·03; p=0·23). At 36 months, 74·2% (95% CI 69·3-78·6) of patients in the selective laser trabeculoplasty group required no drops to maintain intraocular pressure at target. Eyes of patients in the selective laser trabeculoplasty group were within target intracoluar pressure at more visits (93·0%) than in the eye drops group (91·3%), with glaucoma surgery to lower intraocular pressure required in none versus 11 patients. Over 36 months, from an ophthalmology cost perspective, there was a 97% probability of selective laser trabeculoplasty as first treatment being more cost-effective than eye drops first at a willingness to pay of £20 000 per quality-adjusted life-year gained. INTERPRETATION: Selective laser trabeculoplasty should be offered as a first-line treatment for open angle glaucoma and ocular hypertension, supporting a change in clinical practice. FUNDING: National Institute for Health Research, Health and Technology Assessment Programme.

An Intraocular Pressure Polygenic Risk Score Stratifies Multiple Primary Open-Angle Glaucoma Parameters Including Treatment Intensity.

PURPOSE: To examine the combined effects of common genetic variants associated with intraocular pressure (IOP) on primary open-angle glaucoma (POAG) phenotype using a polygenic risk score (PRS) stratification. DESIGN: Cross-sectional study. PARTICIPANTS: For the primary analysis, we examined the glaucoma phenotype of 2154 POAG patients enrolled in the Australian and New Zealand Registry of Advanced Glaucoma, including patients recruited from the United Kingdom. For replication, we examined an independent cohort of 624 early POAG patients. METHODS: Using IOP genome-wide association study summary statistics, we developed a PRS derived solely from IOP-associated variants and stratified POAG patients into 3 risk tiers. The lowest and highest quintiles of the score were set as the low- and high-risk groups, respectively, and the other quintiles were set as the intermediate risk group. MAIN OUTCOME MEASURES: Clinical glaucoma phenotype including maximum recorded IOP, age at diagnosis, number of family members affected by glaucoma, cup-to-disc ratio, visual field mean deviation, and treatment intensity. RESULTS: A dose-response relationship was found between the IOP PRS and the maximum recorded IOP, with the high genetic risk group having a higher maximum IOP by 1.7 mmHg (standard deviation [SD], 0.62 mmHg) than the low genetic risk group (P = 0.006). Compared with the low genetic risk group, the high genetic risk group had a younger age of diagnosis by 3.7 years (SD, 1.0 years; P < 0.001), more family members affected by 0.46 members (SD, 0.11 members; P < 0.001), and higher rates of incisional surgery (odds ratio, 1.5; 95% confidence interval, 1.1-2.0; P = 0.007). No statistically significant difference was found in mean deviation. We further replicated the maximum IOP, number of family members affected by glaucoma, and treatment intensity (number of medications) results in the early POAG cohort (P ≤ 0.01). CONCLUSIONS: The IOP PRS was correlated positively with maximum IOP, disease severity, need for surgery, and number of affected family members. Genes acting via IOP-mediated pathways, when considered in aggregate, have clinically important and reproducible implications for glaucoma patients and their close family members.

Lentiviral Vector-Mediated Expression of Exoenzyme C3 Transferase Lowers Intraocular Pressure in Monkeys.

Primary open-angle glaucoma (POAG) is considered a lifelong disease characterized by optic nerve deterioration and visual field damage. Although the disease progression can usually be controlled by lowering the intraocular pressure (IOP), therapeutic effects of current approaches do not last long. Gene therapy could be a promising method for persistent treatment of the disease. Our previous study demonstrated that gene transfer of exoenzyme C3 transferase (C3) to the trabecular meshwork (TM) to inhibit Rho GTPase (Rho), the upstream signal molecule of Rho-associated kinase (ROCK), resulted in lowered IOP in normal rodent eyes. In the present study, we show that the lentiviral vector (LV)-mediated C3 expression inactivates RhoA in human TM cells by ADP ribosylation, resulting in disruption of the actin cytoskeleton and altered cell morphology. In addition, intracameral delivery of the C3 vector to monkey eyes leads to persistently lowered IOP without obvious signs of inflammation. This is the first report of using a vector to transduce the TM of an alive non-human primate with a gene that alters cellular machinery and physiology. Our results in non-human primates support that LV-mediated C3 expression in the TM may have therapeutic potential for glaucoma, the leading cause of irreversible blindness in humans.