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MiRNAs and Genes Involved in the Interplay between Ocular Hypertension and Primary Open-Angle Glaucoma. Oxidative Stress, Inflammation, and Apoptosis Networks.

ABSTRACT: Glaucoma has no cure and is a sight-threatening neurodegenerative disease affecting more than 100 million people worldwide, with primary open angle glaucoma (POAG) being the most globally prevalent glaucoma clinical type. Regulation of gene expression and gene networks, and its multifactorial pathways involved in glaucoma disease are landmarks for ophthalmic research. MicroRNAs (miRNAs/miRs) are small endogenous non-coding, single-stranded RNA molecules (18-22 nucleotides) that regulate gene expression. An analytical, observational, case-control study was performed in 42 patients of both sexes, aged 50 to 80 years, which were classified according to: (1) suffering from ocular hypertension (OHT) but no glaucomatous neurodegeneration (ND) such as the OHT group, or (2) have been diagnosed of POAG such as the POAG group. Participants were interviewed for obtaining sociodemographic and personal/familial records, clinically examined, and their tear samples were collected and frozen at 80 °C until processing for molecular-genetic assays. Tear RNA extraction, libraries construction, and next generation sequencing were performed. Here, we demonstrated, for the first time, the differential expression profiling of eight miRNAs when comparing tears from the OHT versus the POAG groups: the miR-26b-5p, miR-152-3p, miR-30e-5p, miR-125b-2-5p, miR-224-5p, miR-151a-3p, miR-1307-3p, and the miR-27a-3p. Gene information was set up from the DIANA-TarBase v7, DIANA-microT-CDS, and TargetScan v7.1 databases. To build a network of metabolic pathways, only genes appearing in at least four of the following databases: DisGeNet, GeneDistiller, MalaCards, OMIM PCAN, UniProt, and GO were considered. We propose miRNAs and their target genes/signaling pathways as candidates for a better understanding of the molecular-genetic bases of glaucoma and, in this way, to gain knowledge to achieve optimal diagnosis strategies for properly identifying HTO at higher risk of glaucoma ND. Further research is needed to validate these miRNAs to discern the potential role as biomarkers involved in oxidative stress, immune response, and apoptosis for the diagnosis and/or prognosis of OHT and the prevention of glaucoma ND.

SUBMITTER: Raga-Cervera J

PROVIDER: S-EPMC8196557 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:PurposeTo quantify patients' preferences for glaucoma outcomes and use this information to prioritize outcomes that are important to patients.DesignA cross-sectional study using best-worst scaling object case (BWS).ParticipantsTwo hundred seventy-four participants newly diagnosed with ocular hypertension or mild to moderate open angle glaucoma from three private practices and one academic medical center in the United States.MethodsWe designed a preference-elicitation survey based on findings from 25 semi-structured, qualitative interviews with patients with glaucoma (reported elsewhere). The survey asked participants to rate the importance of 13 glaucoma outcomes on a Likert scale as a warm-up exercise followed by completion of 13 BWS tasks. For each task, we presented participants a subset of four outcomes from the possible thirteen, and participants chose the most important and least important outcome. Outcomes included in the survey pertain to maintaining ability to perform vision-dependent activities of daily living (e.g., driving), maintaining visual function and perception (e.g., depth perception), minimizing need to take glaucoma drops, not experiencing ocular surface symptoms (e.g., red eyes, teary eyes), and having adequate control of intraocular pressure (IOP). We administered the survey online and analyzed response patterns using conditional logistic regression to determine the relative importance of different outcomes.Main outcomeOrdinal ranking of glaucoma outcomes based on preference weights.ResultsBetween September 1, 2017 and February 28, 2018, we invited 1035 patients to complete our survey, among whom 274 (26%) responded. Most participants were older than 65 years of age (146/274, 53%) and currently on IOP-lowering drops (179/274, 65%). Participants identified that outcomes with the largest relative importance weight were having "adequate IOP control" and ability to "drive a car during the day," and the outcomes with the smallest relative importance weights were "maintaining appearance of the eye" and "reducing the number of IOP-lowering drops".ConclusionsDetermining the relative importance of glaucoma outcomes to patients can help researchers design studies that may better inform clinical and regulatory decision-making. Although IOP is an outcome that researchers often measure in glaucoma clinical trials, patients also prioritized outcomes related to the ability to perform vision-dependent activities such as driving.

Project description:IntroductionFixed-combination intraocular pressure (IOP)-lowering medications simplify treatment regimens for patients requiring 2 ocular hypotensive agents to maintain sufficiently low IOP. The aim of this study was to evaluate the safety and efficacy of fixed-combination brinzolamide 1%/brimonidine 0.2% (BBFC) versus concomitant administration of brinzolamide 1% plus brimonidine 0.2% (BRINZ + BRIM) in patients with open-angle glaucoma or ocular hypertension.MethodsThis was a prospective, phase 3, multicenter, double-masked, 6-month trial. Patients who had insufficient IOP control with monotherapy or who were receiving 2 IOP-lowering medications were randomized 1:1 to receive twice-daily BBFC or BRINZ + BRIM. IOP was assessed at 9 a.m. and 11 a.m. during week 2, week 6, month 3, and month 6 visits. The primary efficacy endpoint was mean diurnal IOP change from baseline to month 3; noninferiority was concluded if the upper limit of the 95% CI of the between-group difference was <1.5 mmHg. Supportive endpoints included mean IOP, IOP change from baseline, and percentage of patients with IOP <18 mmHg. Adverse events were recorded.ResultsThe mean diurnal IOP change from baseline with BBFC (least squares mean ± standard error -8.5 ± 0.16 mmHg) was noninferior to that with BRINZ + BRIM (-8.3 ± 0.16 mmHg; mean difference -0.1 mmHg; 95% CI -0.5 to 0.2 mmHg). The upper limits of the 95% CIs were <1.5 mmHg at all time points. Decreases from baseline >8 mmHg were observed for least squares mean diurnal IOP in both groups as early as week 2 and continued to the end of the study. The results of all other supportive endpoints were similar to the primary efficacy endpoint. The most common ocular adverse drug reactions were hyperemia of the eye (reported as ocular or conjunctival hyperemia), visual disturbances, ocular allergic reactions, and ocular discomfort. Common systemic adverse drug reactions included dysgeusia, oral dryness, and fatigue/drowsiness.ConclusionBrinzolamide 1%/brimonidine 0.2% fixed combination was as well tolerated and effective as concomitant therapy with its components. BBFC reduces treatment burden in patients who require multiple IOP-lowering medications.

Project description:Purpose To evaluate the long-term safety of latanoprost benzalkonium chloride (BAK)-free vs currently marketed latanoprost 0.005% ophthalmic solution containing BAK (referred to as reference), to treat open-angle glaucoma (OAG) or ocular hypertension (OHT). Patients and Methods This phase 3, multicenter, open-label, nonrandomized, single group assignment, safety study included patients who previously completed a phase 3 noninferiority study. Patients self-administered 1 drop of latanoprost BAK-free nightly for 36 weeks in the affected eye(s). Intraocular pressure (IOP), visual acuity (VA), and slit lamp biomicroscopy were assessed predose at baseline and Days 28, 56, 84, 112, 140, and 168; dilated ophthalmoscopy and visual field (VF) at baseline and Day 168. Adverse events (AEs) were recorded throughout the study. Results A total of 161 patients who previously received latanoprost BAK-free (n = 80) or reference (n = 81) were enrolled. Latanoprost BAK-free maintained lowered IOP for both the study and nonstudy eye in all patients relative to baseline throughout the study. Clinically significant retinal or optic nerve changes were identified in 5 patients (1 mild-to-moderate change, prior latanoprost BAK-free; 4 mild changes, prior reference). No clinically important changes were identified for VA, slit lamp biomicroscopy, and VF measurements. Ocular AEs occurred in 66 (82.5%) vs 74 (91.4%) patients on prior latanoprost BAK-free and reference, respectively; the most frequent being eye pain (50.0% vs 64.2%) and ocular hyperemia (47.5% vs 54.3%). Most AEs were mild. There were 5 serious systemic AEs in 5 patients (n = 3, prior latanoprost BAK-free; n = 2, prior reference); all were considered unrelated or not likely related to treatment. One patient (prior reference) discontinued due to follicular conjunctivitis. There were no deaths or serious ocular AEs. Conclusion Latanoprost BAK-free was well tolerated. These findings support the chronic use of latanoprost BAK-free to treat OAG or OHT. Clinical Trial Registration Number NCT00945958.

Project description:IntroductionThis study evaluated the intraocular pressure (IOP)-lowering efficacy and safety of a single intracameral administration of bimatoprost implant 10 µg in adults with open-angle glaucoma or ocular hypertension.MethodsTwo identically designed, randomized, 20-month, parallel-group, phase 3 clinical trials (one study eye/patient) compared three administrations of 10- or 15-µg bimatoprost implant (day 1, weeks 16 and 32) with twice-daily topical timolol maleate 0.5%. An open-label, 24-month, phase 1/2 clinical trial compared one or two implants administered in the study eye with once-daily topical bimatoprost 0.03% in the fellow eye. Separate analyses of the pooled phase 3 and phase 1/2 study datasets evaluated outcomes in the 10-µg bimatoprost implant and comparator treatment arms after a single implant administration, up to the time of implant re-administration or rescue with IOP-lowering medication.ResultsIn the phase 3 studies, 10-µg bimatoprost implant single administration demonstrated IOP reductions (hour 0) of 4.9-7.0 mmHg through week 15 from a mean (standard deviation, SD) baseline IOP of 24.5 (2.6) mmHg (n = 374); IOP in the topical timolol BID group was reduced by 6.0-6.3 mmHg from a mean (SD) baseline IOP of 24.5 (2.6) mmHg (n = 373). In the phase 1/2 study (n = 21), median time to use of additional IOP-lowering treatment (Kaplan-Meier analysis) was 273 days (approximately 9 months), and 5 of 21 enrolled patients (23.8%) required no additional IOP-lowering treatment up to 24 months after single administration. In each study, after a single implant administration there were no reports of corneal edema, corneal endothelial cell loss, or corneal touch, and no patients had 20% or greater loss in corneal endothelial cell density.ConclusionsBimatoprost implant single administration lowers IOP and has a favorable safety profile. Additional studies are needed to further evaluate the duration of effect and factors predicting long-term IOP lowering after a single implant administration.Trial registration numbersClinicalTrials.gov NCT02247804, NCT02250651, and NCT01157364.

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MiRNAs and Genes Involved in the Interplay between Ocular Hypertension and Primary Open-Angle Glaucoma. Oxidative Stress, Inflammation, and Apoptosis Networks.

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