Complement cascade inhibition in geographic atrophy: a review

The pathophysiology of dry age-related macular degeneration (AMD) and specifically geographic atrophy (GA) has been linked to the complement cascade. This cascade is part of the innate immune system and is made up of the classical, alternative, and lectin pathways. The pathways comprise a system of plasma and membrane-associated serum proteins that are activated with identification of a nonself entity. A number of these proteins have been implicated in the development and progression of dry AMD. The three pathways converge at C3 and cascade down through C5, making both of these proteins viable targets for the treatment of dry AMD. In addition, there are a number of complement factors, CFB, CFD, CFH, and CFI, which are potential therapeutic targets as well. Several different complement-directed therapeutics are being studied for the treatment of dry AMD with the hope that one of these approaches will emerge as the first approved treatment for GA.

Machine-learning and Automatically Segmented Retinal Biomarkers Generate Spatial Heatmaps Predictive for Standard and Low Luminance Visual Acuity in Geographic Atrophy

Objective: Predict visual function with machine-learning applied to automatically acquired quantitative imaging biomarkers in geographic atrophyDesign: Post-hoc analysis of data from a clinical trial and routine clinical care.Methods: Automated segmentation of OCT scans from 476 eyes (325 patients) with geographic atrophy. Machine learning modelling of resultant quantitative OCT (qOCT) biomarkers to predict cross-sectional visual acuity under both standard luminance (VA) and low luminance (LLVA) conditions.Main Outcome Measure: Correlation coefficient (R2) and mean absolute error (MAE) for cross-sectional VA and LLVA in Early Treatment Diabetic Retinopathy Study (ETDRS) letters.Results: Best-corrected VA under both standard luminance (R2 0.46 MAE 10.2 ETDRS letters) and low-luminance conditions (R2 0.25 MAE 12.1) could be predicted. The foveal region contributed the most (46.5%) toward model performance, with retinal pigment epithelium loss and outer retinal atrophy contributing the most (31.1%). For LLVA, however, features in the non-foveal regions were most important (74.5%), led by photoreceptor degeneration (38.9%).Conclusions: Our method of automatic qOCT segmentation demonstrates functional significance for vision in geographic atrophy, including LLVA. LLVA is itself predictive of geographic atrophy progression, implying that the predictive qOCT biomarkers provided by our model are also prognostic.

Ophthalmic artery angioplasty for age-related macular degeneration

BackgroundThere is considerable overlap of contributors to cardiovascular disease and the development of age-related macular degeneration (AMD). Compromised ocular microcirculation due to aging and vascular disease contribute to retinal dysfunction and vision loss. Decreased choroidal perfusion is evident in eyes with dry AMD and is thought to play a role in retinal pigment epithelial dysfunction, the rate of development of geographic atrophy, and the development of neovascularization. The aim of the study was to demonstrate that AMD is correlated with a compromised blood flow in the ocular pathway and show OA angioplasty as a potential treatment of late-stage AMD.MethodsBased on the potential for the ophthalmic artery (OA) to be an anatomical target for the treatment of AMD as outlined above, five patients were found to be eligible for compassionate use treatment, presenting clinically significant late-stage AMD with profound vision loss in one or both eyes, and are included in this retrospective study.ResultsOA narrowing, or significant calcium burden at the ophthalmic segment of the internal carotid artery compromising the origin of the OA was confirmed in all cases. Subsequent OA cannulation was achieved in all patients with some difficulty. Subjective patient reports indicated that all patients perceived a benefit following the procedure; however, improved postoperative visual acuity did not confirm that perceived benefit for one of the patients.ConclusionsFeasibility and safety of the OA angioplasty were demonstrated, and a benefit perceived in five patients with profound vision loss and a desire to achieve improved quality of life. A clinical trial with controlled schedule, imaging, and methodologies is needed to confirm these results.