Lentiviral mediated delivery of CRISPR/Cas9 reduces intraocular pressure in a mouse model of myocilin glaucoma.

Mutations in myocilin (MYOC) are the leading known genetic cause of primary open-angle glaucoma, responsible for about 4% of all cases. Mutations in MYOC cause a gain-of-function phenotype in which mutant myocilin accumulates in the endoplasmic reticulum (ER) leading to ER stress and trabecular meshwork (TM) cell death. Therefore, knocking out myocilin at the genome level is an ideal strategy to permanently cure the disease. We have previously utilized CRISPR/Cas9 genome editing successfully to target MYOC using adenovirus 5 (Ad5). However, Ad5 is not a suitable vector for clinical use. Here, we sought to determine the efficacy of adeno-associated viruses (AAVs) and lentiviruses (LVs) to target the TM. First, we examined the TM tropism of single-stranded (ss) and self-complimentary (sc) AAV serotypes as well as LV expressing GFP via intravitreal (IVT) and intracameral (IC) injections. We observed that LV_GFP expression was more specific to the TM injected via the IVT route. IC injections of Trp-mutant scAAV2 showed a prominent expression of GFP in the TM. However, robust GFP expression was also observed in the ciliary body and retina. We next constructed lentiviral particles expressing Cas9 and guide RNA (gRNA) targeting MYOC (crMYOC) and transduction of TM cells stably expressing mutant myocilin with LV_crMYOC significantly reduced myocilin accumulation and its associated chronic ER stress. A single IVT injection of LV_crMYOC in Tg-MYOCY437H mice decreased myocilin accumulation in TM and reduced elevated IOP significantly. Together, our data indicates, LV_crMYOC targets MYOC gene editing in TM and rescues a mouse model of myocilin-associated 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.

The Finnish current care guideline for open-angle glaucoma.

This article is an English translation of the 4th Finnish Current Care Guideline for diagnostics, treatment and follow-up of primary open-angle glaucoma, normal-tension glaucoma and pseudoexfoliative glaucoma. This guideline is based on systematic literature reviews and expert opinions with Finland's geographical and operational healthcare environment in mind.

Targeted Telephone-Based Outreach Reconnects Glaucoma Patients With Subspecialty Care.

PRCIS: A personalized telephone-based intervention is a cost-effective method to return overdue patients with open angle glaucoma (OAG) to subspecialty care. Patients who accepted care overwhelmingly preferred in-person appointments with their provider instead of hybrid visits with telehealth. PURPOSE: To evaluate the effectiveness of a telephone-based outreach strategy to reconnect OAG patients with subspeciality care. PATIENTS AND METHODS: Established patients with OAG who were seen before March 1, 2021, but had not returned for care in the following year were contacted via a telephone-based intervention. Patients lost to follow-up (LTF) were offered the option of an in-person visit or a hybrid telehealth visit, which combined in-office testing of vision, intraocular pressure, and optic nerve imaging with a virtual consultation with their glaucoma specialist on a separate date. RESULTS: Of 2727 patients with OAG, 351 (13%) had not returned for recommended care. Outbound calls reached 176 of those patients (50%). Nearly half of all patients contacted readily accepted care, with 71 scheduling in-person appointments (93%) and 5 selecting hybrid visits (6.6%). Medication refills were requested by 17 of those 76 patients, representing nearly a third of the 56 patients who were treated with topical glaucoma medications. Assessment of the program 90 days later found that 40 patients had returned for care, 100 patients had transferred or declined further care, and 40 patients were identified as deceased, lowering the LTF rate to 6.4%, with 15 patients still scheduled for future visits. On the basis of an average call duration of 2.8±2.0 minutes, the added cost of returning a patient with OAG to care by the program was $28.11. CONCLUSIONS: Providing targeted outreach by telephone is an effective and cost-efficient strategy to reconnect OAG patients LTF with subspecialty care.

Pseudoexfoliation Glaucoma: Clinical Presentation and Therapeutic Options.

Pseudoexfoliation syndrome (PES) is one of the most common causes of open-angle glaucoma, with a higher risk of vision loss, a higher maximum and mean intraocular pressure (IOP) at diagnosis, and a wider range of IOP fluctuation compared to primary open-angle glaucoma. Patients with this syndrome have a ten-fold higher risk of developing glaucoma than the normal population. A definite diagnosis can be made by the observation of pseudoexfoliation material (PEM) on the anterior lens surface, ciliary processes, zonules, and iris. PEM deposits on the zonules may explain the clinically observed zonular weakness and lens subluxation or dislocation. An increased incidence of cataract development is also associated with PES. There is growing evidence for systemic associations of PES with peripheral, cardiovascular, and cerebrovascular system diseases, Alzheimer's disease, hearing loss, and increased plasma homocysteine levels. Indications for surgery are markedly more common in patients with pseudoexfoliation glaucoma than primary open-angle glaucoma. The goal of this article is to review the latest perspectives on the clinical features, therapy, and systemic associations of this clinically and biologically challenging disease.

Identification and validation of key biomarkers and potential therapeutic targets for primary open-angle glaucoma.

Primary open-angle glaucoma (POAG) is a prevalent cause of blindness worldwide, resulting in degeneration of retinal ganglion cells and permanent damage to the optic nerve. However, the underlying pathogenetic mechanisms of POAG are currently indistinct, and there has been no effective nonsurgical treatment regimen. The objective of this study is to identify novel biomarkers and potential therapeutic targets for POAG. The mRNA expression microarray datasets GSE27276 and GSE138125, as well as the single-cell high-throughput RNA sequencing (scRNA-seq) dataset GSE148371 were utilized to screen POAG-related differentially expressed genes (DEGs). Functional enrichment analyses, protein-protein interaction (PPI) analysis, and weighted gene co-expression network analysis (WGCNA) of the DEGs were performed. Subsequently, the hub genes were validated at a single-cell level, where trabecular cells were annotated, and the mRNA expression levels of target genes in different cell clusters were analyzed. Immunofluorescence and quantitative real-time PCR (qPCR) were performed for further validation. DEGs analysis identified 43 downregulated and 32 upregulated genes in POAG, which were mainly enriched in immune-related pathways, oxidative stress, and endoplasmic reticulum (ER) stress. PPI networks showed that FN1 and DUSP1 were the central hub nodes, while GPX3 and VAV3 were screened out as hub genes through WGCNA and subsequently validated by qPCR. Finally, FN1, GPX3, and VAV3 were determined to be pivotal core genes via single-cell validation. The relevant biomarkers involved in the pathogenesis of POAG, may serve as potential therapeutic targets. Further studies are necessary to unveil the mechanisms underlying the expression variations of these genes in 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.

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.

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.

A Review of Cost-Effectiveness Analyses for Open Angle Glaucoma Management.

PURPOSE: Cost-effectiveness analyses (CEAs) quantify and compare both costs and measures of efficacy for different interventions. As the costs of glaucoma management to patients, payers, and physicians are increasing, we seek to investigate the role of CEAs in the field of glaucoma and how such studies impact clinical management. METHODS: We adhered to the "Preferred Reporting Items for Systematic Reviews and Meta-analyses" guidelines for our systematic review structure. Eligible studies included any full-text articles that investigated cost-effectiveness or cost-utility as it relates to the field of open angle glaucoma management in the United States. Risk of bias assessment was conducted using the validated Joanna Briggs Institute Critical Appraisal Checklist for Economic Evaluations. RESULTS: Eighteen studies were included in the review. Dates of publication ranged from 1983 to 2021. Most of the studies were published in the 2000s and performed CEAs in the domains of treatment/therapy, screening, and adherence for patients with primary angle open glaucoma. Of the 18 articles included, 14 focused on treatment, 2 on screening, and 2 on adherence. Most of these studies focused on the cost-effectiveness of different topical medical therapies, whereas only a few studies explored laser procedures, surgical interventions, or minimally invasive procedures. Economic models using decision analysis incorporating state-transition Markov cycles or Montecarlo simulations were widely used, however, the methodology among studies was variable, with a wide spectrum of inputs, measures of outcomes, and time horizons used. CONCLUSION: Overall, we found that cost-effectiveness research in glaucoma in the United States remains relatively unstructured, resulting in unclear and conflicting implications for clinical management.

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.

Encounter glaucoma decision Aid trial.

PURPOSE: A decision aid facilitates patient engagement in the decision-making process in ophthalmic practice. In particular, patients with open-angle glaucoma will benefit from such an intervention as it enhances their knowledge, compliance, and satisfaction with the healthcare services. METHODS: The Encounter Glaucoma Decision Aid (GDA) was delivered to 145 patients with open-angle glaucoma at the King Khaled Eye Specialist Hospital. Evaluation was done using a pre-validated, semi-structured questionnaire. We compared the patients' knowledge, compliance, and decision conflict scale at baseline, before receiving Encounter GDA, and again three months later. RESULTS: The average age of the participants was 56.82 years. Most of the participants were male (67.6%). The mean duration since the participants were diagnosed with glaucoma was 9.39 years. After using Encounter GDA, 80% of participants had a statistically significant improvement in their level of knowledge, moving from poor to good (P = 0.001). There was also a statistically significant increase in adherence to medication, from 41.4% to 65.5% (P = 0.001). The decision conflict score decreased significantly after using Encounter GDA (before it was 60.94 ± 21.60 vs. after 19.18 ± 17.83). CONCLUSION: Using GDA cards as an educational measure has a significant effect on improving patient's knowledge and adherence to medications.

Analysis of aerobic exercise influence on intraocular pressure and ocular perfusion pressure in patients with primary open-angle glaucoma: A randomized clinical trial.

Purpose: To investigate the change pattern of ocular perfusion pressure (OPP) and intra-ocular pressure (IOP) after short-term and long-term aerobic exercise. Methods: In this prospective, single-masked, randomized clinical trial, 123 patients with a primary open angle glaucoma that locally used prostaglandin analog alone were randomly divided into the exercise and control groups. In the short-term study, all individuals underwent a cycling exercise at moderate intensity (20% Wmax for 10 minutes) and high intensity (60% Wmax for 5 minutes). During the long-term study, the exercise group is characterized by regular jogging exercise lasting for 30 minutes during 6: 00-10: 00 in the morning for 3 months, with the exercise frequency of at least 20 times per month, and with the intensity reflected by the target heart rate. The control group is designed as a group with irregular exercise. Results: After short-term aerobic exercise, IOP significantly decreased, whereas the ocular perfusion pressure (OPP) significantly increased. The decreasing amplitude of IOP is related to the baseline of IOP, the intensity of exercise, gender, and so on. After 3 months of long-term exercise, the changes in the IOP level of the exercise group indicated a decreasing trend. Conclusion: The significant decrement of IOP and the increment of OPP suggest that aerobic exercise is beneficial for patients with primary open-angle glaucoma and appropriate aerobic exercise is appropriate in treating glaucoma patients. Trial registration: ChiCTR, ChiCTR-TRC-10001055. Registered one October 2010-Retrospectively registered, http://www.chictr.org.cn/showproj.aspx?proj = 8483.

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.

Adult Eye Conditions: Primary Open-Angle Glaucoma and Cataract.

Primary open-angle glaucoma (POAG) is a progressive, chronic, irreversible ocular disease that leads to loss of visual field. In the United States, its prevalence is expected to more than double from 2011 to 2050. POAG is three times more common among Black people than White people. More than half of patients with POAG are asymptomatic. Management focuses on decreasing intraocular pressure. Prostaglandin analogue eye drops can preserve visual field and are the first-line therapy. There currently is no evidence to support universal screening for POAG in adults. Physicians should recognize patients at high risk and provide early referral to an ophthalmologist. They also should encourage patients with POAG to adhere to treatment and follow up with their ophthalmologist. Cataract is a progressive condition caused by opacification of the lens of the eye. It affects 24.4 million Americans and is expected to affect 50 million Americans by 2050. Patients with cataracts present with visual impairment, glare, decreased color and contrast sensitivity, and poor adaptation to darkness. Management consists of surgical removal of the lens via small-incision phacoemulsification with placement of a foldable intraocular lens. After surgery, patients may develop posterior capsular opacification, which can be managed with laser capsulotomy.

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.

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.

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).