Deuterated polyunsaturated fatty acids provided protection against oxidative stress in ocular fibroblasts derived from glaucoma patients

Glaucoma is a complex neurodegenerative disease of the optic nerve that leads to irreversible sight loss. Lowering intraocular pressure (IOP) medically or surgically represents the mainstay of treatment but despite adequate treatment optic nerve function can continue to deteriorate leading to blindness. There is significant clinical and experimental evidence that oxidative stress is involved in the pathogenesis of glaucoma. Decreasing the formation of lipid peroxidation products or scavenging them chemically could be beneficial in limiting the deleterious effects of oxidative stress in glaucoma. A solution to control the susceptibility of PUFAs to noxious lipid peroxidation reactions is by regioselective deuteration. Deuterium incorporated into PUFAs at bis-allylic positions (D-PUFAs) inhibits the rate-limiting step of lipid peroxidation. In this study, we have shown that Tenon's ocular fibroblasts from glaucoma patients have significantly increased basal oxidative stress compared to non-glaucomatous control patients. Furthermore, we have shown that deuterated polyunsaturated fatty acids (D-PUFAs) provide an enhanced rescue of menadione induced lipid peroxidation in both non-glaucomatous and glaucomatous Tenon's ocular fibroblasts using malondialdehyde (MDA) levels as a marker. Our study suggests that D- PUFAs may provide a potentially safe and effective method to reduce cytotoxic oxidative stress in glaucoma

Corneal Endothelial Cell Loss in Glaucoma and Glaucoma Surgery and the Utility of Management with Descemet Membrane Endothelial Keratoplasty (DMEK)

Publisher Copyright: © 2022 Neeru A Vallabh et al.The corneal endothelium has a crucial role in maintaining a clear and healthy cornea. Corneal endothelial cell loss occurs naturally with age; however, a diagnosis of glaucoma and surgical intervention for glaucoma can exacerbate a decline in cell number and impairment in morphology. In glaucoma, the mechanisms for this are not well understood and this accelerated cell loss can result in corneal decompensation. Given the high prevalence of glaucoma worldwide, this review aims to explore the abnormalities observed in the corneal endothelium in differing glaucoma phenotypes and glaucoma therapies (medical or surgical including with new generation microinvasive glaucoma surgeries). Descemet membrane endothelial keratoplasty (DMEK) is increasingly being used to manage corneal endothelial failure for glaucoma patients and we aim to review the recent literature evaluating the use of this technique in this clinical scenario.publishersversionPeer reviewe

Optic neuropathies that mimic glaucoma.

It can be difficult to tell the difference between a glaucomatous optic nerve and a glaucoma mimic. Here are some tips that well help you to avoid diagnosing glaucoma when there is something else going on

Solar retinopathy: a new setting of red, green, and blue channels

Purpose: To introduce a new color imaging technique using improved settings of red, green, and blue channels for improved delineation of retinal damage in patients with solar retinopathy. Method: A retrospective case series of patients with poor vision secondary to solar retinopathy were analyzed. All patients underwent visual acuity, refraction, and dilated fundus examination. A spectral domain–optical coherence tomography of the macula and color fundus imaging using optimized red, green, and blue color setting was performed. Patients were reviewed over a 6-month period. The data were analyzed for statistical significance using an independent t test and a receiver operating characteristic curve. Results: In total, 20 eyes of 10 patients were included between 2009 and 2017. The mean age was 24.9 ± 18.1 years. Best corrected visual acuity at first consultation was 0.78 ± 0.11 and after 6 months was 0.83 ± 0.09. Spectral domain–optical coherence tomography demonstrated retinal abnormalities at the myoid zone, ellipsoid zone, and the outer segment of photoreceptors. Receiver operating characteristic curve analysis showed an improving effect (area under the curve = 0.62; 95% confidence interval = 0.42–0.79). The color channels parameters, which improve visualization of the lesions were found to be 67-0.98-255 for the R-guided setting, 19-0.63-121 for the B-guided setting, and 7-1.00-129 for the G-guided setting. The ideal red, green, and blue setting was in 24-0.82-229. Conclusion: The use of a new setting of red, green, and blue channels could improve the diagnosis and monitoring of solar retinopathy, hence improving patient care

Corneal Endothelial Cell Loss in Glaucoma and Glaucoma Surgery and the Utility of Management with Descemet Membrane Endothelial Keratoplasty (DMEK)

The corneal endothelium has a crucial role in maintaining a clear and healthy cornea. Corneal endothelial cell loss occurs naturally with age; however, a diagnosis of glaucoma and surgical intervention for glaucoma can exacerbate a decline in cell number and impairment in morphology. In glaucoma, the mechanisms for this are not well understood, and this accelerated cell loss can result in corneal decompensation. Given the high prevalence of glaucoma worldwide, this review aims to explore the abnormalities observed in the corneal endothelium in differing glaucoma phenotypes and glaucoma therapies (medical or surgical, including with new generation microinvasive glaucoma surgeries). Descemet membrane endothelial keratoplasty (DMEK) is increasingly being used to manage corneal endothelial failure for glaucoma patients, and we aim to review the recent literature evaluating the use of this technique in this clinical scenario.</jats:p

Non-Viral Gene Therapy in Trabecular Meshwork Cells to Prevent Fibrosis in Minimally Invasive Glaucoma Surgery

The primary cause of failure for minimally invasive glaucoma surgery (MIGS) is fibrosis in the trabecular meshwork (TM) that regulates the outflow of aqueous humour, and no anti-fibrotic drug is available for intraocular use in MIGS. The myocardin-related transcription factor/serum response factor (MRTF/SRF) pathway is a promising anti-fibrotic target. This study aims to utilise a novel lipid nanoparticle (LNP) to deliver MRTF-B siRNA into human TM cells and to compare its effects with those observed in human conjunctival fibroblasts (FF). Two LNP formulations were prepared with and without the targeting peptide c&Upsilon;, and with an siRNA concentration of 50 nM. We examined the biophysical properties and encapsulation efficiencies of the LNPs, and evaluated the effects of MRTF-B silencing on cell viability, key fibrotic genes expression and cell contractility. Both LNP formulations efficiently silenced MRTF-B gene and were non-cytotoxic in TM and FF cells. The presence of c&Upsilon; made the LNPs smaller and more cationic, but had no significant effect on encapsulation efficiency. Both TM and FF cells also showed significantly reduced contractibility after transfection with MRTF-B siRNA LNPs. In TM cells, LNPs with c&Upsilon; achieved a greater decrease in contractility compared to LNPs without c&Upsilon;. In conclusion, we demonstrate that the novel CL4H6-LNPs are able to safely and effectively deliver MRTF-B siRNA into human TM cells. LNPs can serve as a promising non-viral gene therapy to prevent fibrosis in MIGS

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

Multitrait analysis of glaucoma identifies new risk loci and enables polygenic prediction of disease susceptibility and progression

Glaucoma, a disease characterized by progressive optic nerve degeneration, can be prevented through timely diagnosis and treatment. We characterize optic nerve photographs of 67,040 UK Biobank participants and use a multitrait genetic model to identify risk loci for glaucoma. A glaucoma polygenic risk score (PRS) enables effective risk stratification in unselected glaucoma cases and modifies penetrance of the MYOC variant encoding p.Gln368Ter, the most common glaucoma-associated myocilin variant. In the unselected glaucoma population, individuals in the top PRS decile reach an absolute risk for glaucoma 10 years earlier than the bottom decile and are at 15-fold increased risk of developing advanced glaucoma (top 10% versus remaining 90%, odds ratio = 4.20). The PRS predicts glaucoma progression in prospectively monitored, early manifest glaucoma cases (P = 0.004) and surgical intervention in advanced disease (P = 3.6 × 10). This glaucoma PRS will facilitate the development of a personalized approach for earlier treatment of high-risk individuals, with less intensive monitoring and treatment being possible for lower-risk groups