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Purpose: This work aims to review the principles of optical coherence tomography angiography (OCTA), to survey its clinical utility, and to highlight the strengths of this technology as well as barriers to adoption., Methods: A literature review with editorial discussion of the current applications for OCTA is presented., Results: There have been recent advances in multiple domains in OCTA imaging, including devices, algorithms, and new observations pertaining to a range of pathologies. New devices have improved the scanning speed, signal-to-noise ratio, and spatial resolution and offer an increased field of view. New algorithms have been proposed to optimize image processing and reduce artifacts. Numerous studies employing OCTA have been published describing changes to the microvasculature in diabetic retinopathy, age-related macular degeneration, central serous chorioretinopathy, retinal vein occlusion, and uveitis., Conclusions: OCTA provides noninvasive, high-resolution volumetric scans of the retinal and choroidal vasculature. OCTA can provide valuable data to augment traditional dye-based angiography in a range of chorioretinal diseases., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2022.)

Purpose: This work aims to evaluate the clinical utility and feasibility of a novel scanning laser ophthalmoscope-based navigated ultra-widefield swept-source optical coherence tomography (UWF SS-OCT) imaging system., Methods: A retrospective, single-center, consecutive case series evaluated patients between September 2019 and October 2020 with UWF SS-OCT (modified Optos P200TxE, Optos PLC) as part of routine retinal care. The logistics of image acquisition, interpretability of images captured, nature of the peripheral abnormality, and clinical utility in management decisions were recorded., Results: Eighty-two eyes from 72 patients were included. Patients were aged 59.4 ± 17.1 years (range, 8-87 years). During imaging, 4.4 series of images were obtained in 4.1 minutes, with 86.4% of the image series deemed to be diagnostic of the peripheral pathology on blinded image review. The most common pathologic findings were chorioretinal scars (18 eyes). In 31 (38%) eyes, these images were meaningful in supporting clinical decision-making with definitive findings. Diagnoses imaged included retinal detachment combined with retinoschisis, retinal hole with overlying vitreous traction and subretinal fluid, vitreous inflammation overlying a peripheral scar, Coats disease, and peripheral retinal traction in sickle cell retinopathy., Conclusions: Navigated UWF SS-OCT imaging was clinically practical and provided high-quality characterization of peripheral retinal lesions for all eyes. Images directly contributed to management plans, including laser, injection or surgical treatment, for a clinically meaningful set of patients (38%). Future studies are needed to further assess the value of this imaging modality and its role in diagnosing, monitoring, and treating peripheral lesions., Competing Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: S.K. declared consulting and research funding from Optos (research funding was not received for the development of this study). He has also served as a consultant for Adverum, Alcon, Novartis, and Genentech/Roche; received research funding from Allergan, Novartis, Genentech/Roche, and Regeneron; received equity from Adverum, Regenxbio, and Fortress Bio; and intellectual property—gene therapy for age-related macular degeneration, and T cells for CMV retinitis—assigned to Cornell University. K.D.K. has served as a consultant for Regenxbio. D.J.D. has served as a consultant for Alcon, Iveric bio, and Aufbao Holdings; received equity from Iveric bio and Aufbau Holdings; and holds intellectual property for Aufbau Holdings. The other authors have nothing to declare., (© The Author(s) 2021.)

Recessive Stargardt disease (STGD1) is an inherited blinding disorder caused by mutations in the Abca4 gene. ABCA4 is a flippase in photoreceptor outer segments (OS) that translocates retinaldehyde conjugated to phosphatidylethanolamine across OS disc membranes. Loss of ABCA4 in Abca4 -/- mice and STGD1 patients causes buildup of lipofuscin in the retinal pigment epithelium (RPE) and degeneration of photoreceptors, leading to blindness. No effective treatment currently exists for STGD1. Here we show by several approaches that ABCA4 is additionally expressed in RPE cells. ( i ) By in situ hybridization analysis and by RNA-sequencing analysis, we show the Abca4 mRNA is expressed in human and mouse RPE cells. ( ii ) By quantitative immunoblotting, we show that the level of ABCA4 protein in homogenates of wild-type mouse RPE is about 1% of the level in neural retina homogenates. ( iii ) ABCA4 immunofluorescence is present in RPE cells of wild-type and Mertk -/- but not Abca4 -/- mouse retina sections, where it colocalizes with endolysosomal proteins. To elucidate the role of ABCA4 in RPE cells, we generated a line of genetically modified mice that express ABCA4 in RPE cells but not in photoreceptors. Mice from this line on the Abca4 -/- background showed partial rescue of photoreceptor degeneration and decreased lipofuscin accumulation compared with nontransgenic Abca4 -/- mice. We propose that ABCA4 functions to recycle retinaldehyde released during proteolysis of rhodopsin in RPE endolysosomes following daily phagocytosis of distal photoreceptor OS. ABCA4 deficiency in the RPE may play a role in the pathogenesis of STGD1., Competing Interests: The authors declare no conflict of interest., (Copyright © 2018 the Author(s). Published by PNAS.)

Recessive Stargardt macular degeneration (STGD1) is caused by mutations in the gene for the ABCA4 transporter in photoreceptor outer segments. STGD1 patients and Abca4 -/- (STGD1) mice exhibit buildup of bisretinoid-containing lipofuscin pigments in the retinal pigment epithelium (RPE), increased oxidative stress, augmented complement activation and slow degeneration of photoreceptors. A reduction in complement negative regulatory proteins (CRPs), possibly owing to bisretinoid accumulation, may be responsible for the increased complement activation seen on the RPE of STGD1 mice. CRPs prevent attack on host cells by the complement system, and complement receptor 1-like protein y (CRRY) is an important CRP in mice. Here we attempted to rescue the phenotype in STGD1 mice by increasing expression of CRRY in the RPE using a gene therapy approach. We injected recombinant adeno-associated virus containing the CRRY coding sequence (AAV-CRRY) into the subretinal space of 4-wk-old Abca4 -/- mice. This resulted in sustained, several-fold increased expression of CRRY in the RPE, which significantly reduced the complement factors C3/C3b in the RPE. Unexpectedly, AAV-CRRY-treated STGD1 mice also showed reduced accumulation of bisretinoids compared with sham-injected STGD1 control mice. Furthermore, we observed slower photoreceptor degeneration and increased visual chromophore in 1-y-old AAV-CRRY-treated STGD1 mice. Rescue of the STGD1 phenotype by AAV-CRRY gene therapy suggests that complement attack on the RPE is an important etiologic factor in STGD1. Modulation of the complement system by locally increasing CRP expression using targeted gene therapy represents a potential treatment strategy for STGD1 and other retinopathies associated with complement dysregulation.