Impact of Prophylactic Ranibizumab to Prevent Neovascular Age-Related Macular Degeneration on Eyes With Intermediate Age-Related Macular Degeneration.

PURPOSE: The purpose of this study was to determine the impact of prophylactic ranibizumab (PR) injections given every 3 months in eyes with intermediate nonexudative age-related macular degeneration (AMD) on drusen volume, macular layer thicknesses, and progression of geographic atrophy (GA) area over 24 months in the PREVENT trial. METHODS: This post hoc analysis of the prospective PREVENT trial compared eyes with intermediate AMD randomized to PR versus sham injections to determine rates of conversion to neovascular AMD over 24 months. Drusen area and volume, macular thickness and volume, and retinal layer thicknesses were measured on spectral-domain optical coherence tomography images and analyzed. Masked grading of GA area and subretinal drusenoid deposits (SDDs) using fundus autofluorescence images was performed. RESULTS: There were no statistical differences in drusen area and volumes between groups, and similar reductions in central subfield thickness, mean cube thickness, cube volume, and retinal sublayer thickness from baseline to 24 months (P = 0.018 to < 0.001), with no statistical differences between groups in any of these anatomic parameters. These findings were not impacted by the presence or absence of SDD. Among the 9 eyes with GA in this study, mean GA growth rate from baseline to 24 months was 1.34 +/- 0.79 mm2/year after PR and 1.95 +/- 1.73 mm2/year in sham-treated eyes (P = 0.49), and similarly showed no statistical difference with square root transformation (P = 0.61). CONCLUSIONS: Prophylactic ranibizumab given every 3 months did not appear to affect drusen volume, macular thinning, or GA progression in eyes with intermediate AMD. TRANSLATIONAL RELEVANCE: This work investigates the impact of PR on progressive retinal degeneration in a clinical trial

A review of management strategies for nociceptive and neuropathic ocular surface pain

Despite being a common presenting symptom to eye-care clinics, many ophthalmologists have difficulty diagnosing and managing ocular surface pain. The purpose of this review is to discuss potential causes of ocular surface pain, focusing on both nociceptive and neuropathic aetiologies. Specifically, we outline an approach to the diagnosis of ocular surface pain and focus on various management strategies, providing supporting evidence on the efficacy of various treatments

Natural History and Predictors of Vision Loss in Eyes with Diabetic Macular Edema and Good Initial Visual Acuity

PURPOSE: To identify clinical and anatomic factors associated vision loss in eyes with treatment-naïve diabetic macular edema (DME) and good initial visual acuity (VA). METHODS: Retrospective cohort study following long-term history of eyes with untreated center-involving DME and baseline VA ≥ 20/25 seen at the University of California, Davis Eye Center between March 2007-March 2018. We collected characteristics including diabetes type, hemoglobin A1c, presence of visual symptoms, VA, and diabetic retinopathy (DR) severity; and spectral domain-optical coherence tomography (SD-OCT) biomarkers including central subfield thickness (CST), intraretinal cyst size, intraretinal hyperreflective foci, disorganization of retinal inner layers, and outer layer disruptions to determine factors associated with vision loss as defined by DRCR Protocol V as threshold for initiating aflibercept therapy. RESULTS: 56 eyes (48 patients) with untreated DME and mean baseline VA of logMAR 0.05 ± 0.05 (Snellen 20/22) was followed for an average of 5.1 ± 3.3 years, with a median time to vision loss of 465 days (15 months). Older age (hazard ratio (HR) 1.04/year, P = 0.0195), and eyes with severe NPDR (HR 3.0, P = 0.0353) or proliferative DR (HR 7.7, P = 0.0008) had a higher risk of a vision loss event. None of the SD-OCT biomarkers were associated with vision loss except CST (HR 0.98, P = 0.0470) and cyst diameter (HR 1.0, P = 0.0094). CONCLUSIONS: In eyes with DME and good initial vision, those with older age and worse DR severity should be monitored closely for prompt treatment initiation when vision loss occurs

CRISPR-based VEGF suppression using paired guide RNAs for treatment of choroidal neovascularization.

Clustered regularly interspaced short palindromic repeats (CRISPR)-based genomic disruption of vascular endothelial growth factor A (Vegfa) with a single gRNA suppresses choroidal neovascularization (CNV) in preclinical studies, offering the prospect of long-term anti-angiogenesis therapy for neovascular age-related macular degeneration (AMD). Genome editing using CRISPR-CRISPR-associated endonucleases (Cas9) with multiple guide RNAs (gRNAs) can enhance gene-ablation efficacy by augmenting insertion-deletion (indel) mutations with gene truncations but may also increase the risk of off-target effects. In this study, we compare the effectiveness of adeno-associated virus (AAV)-mediated CRISPR-Cas9 systems using single versus paired gRNAs to target two different loci in the Vegfa gene that are conserved in human, rhesus macaque, and mouse. Paired gRNAs increased Vegfa gene-ablation rates in human cells in vitro but did not enhance VEGF suppression in mouse eyes in vivo. Genome editing using paired gRNAs also showed a similar degree of CNV suppression compared with single-gRNA systems. Unbiased genome-wide analysis using genome-wide unbiased identification of double-stranded breaks (DSBs) enabled by sequencing (GUIDE-seq) revealed weak off-target activity arising from the second gRNA. These findings suggest that in vivo CRISPR-Cas9 genome editing using two gRNAs may increase gene ablation but also the potential risk of off-target mutations, while the functional benefit of targeting an additional locus in the Vegfa gene as treatment for neovascular retinal conditions is unclear