Multimodal Structural and Functional Characterization of Retinal Vasculopathy with Cerebral Leukoencephalopathy.

OBJECTIVE: To describe and quantify the structural and functional consequences of retinal vasculopathy with cerebral leukoencephalopathy (RVCL) on the neurosensory retina. DESIGN: Cross sectional descriptive study from December 2021 to December 2022. PARTICIPANTS: Retinal vasculopathy with cerebral leukoencephalopathy patients (n = 9, 18 eyes) recruited from the RVCL Research Center at Washington University in St. Louis. METHODS: Retinal vasculopathy with cerebral leukoencephalopathy patients underwent comprehensive ophthalmological evaluation including OCT, OCT angiography (OCTA), ultrawidefield fundus imaging, retinal autofluorescence, dark adaptation, electroretinography (ERG), Goldmann kinetic perimetry, and fluorescein angiography (FA). MAIN OUTCOME MEASURES: Comprehensive characterization from various modalities including best-corrected visual acuity, central subfield thickness (µm) from OCT, foveal avascular zone (mm2) from OCTA, dark adaptation rod intercept (seconds), cone response in ERG, and presence or absence of vascular abnormalities, leakage, neovascularization, and nonperfusion on FA. RESULTS: A total of 18 eyes from 9 individuals were included in this study. The best-corrected visual acuity ranged from 20/15 to 20/70. The mean central subfield thickness from OCT was 275.8 µm (range, 217-488 µm). The mean foveal avascular zone (FAZ) from OCTA was 0.65 (range, 0.18-1.76) mm2. On dark adaptometry, the mean time was 5.02 (range, 2.9-6.5) minutes, and 1 individual had impaired dark adaptation. Electroretinography demonstrated mild cone response impairment in 4 eyes. On FA, there was evidence of macular and peripheral capillary nonperfusion in 16 of 18 eyes and notable areas of vascular leakage and retinal edema in 5 of the 18 eyes. CONCLUSIONS: This study illustrates the phenotypic spectrum of disease and may be clinically valuable for aiding diagnosis, monitoring disease progression, and further elucidating the pathophysiology of RVCL to aid in the development of therapies. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Cell-specific Systemic Immune Signatures Associated with Treatment Burden in Neovascular Age-related Macular Degeneration.

Purpose: Choroidal neovascularization (CNV) accounts for the majority of severe vision loss in neovascular age-related macular degeneration (AMD). Despite therapies that target VEGF, patients are often under-responsive, require frequent eye injections to control disease, and eventually lose some vision despite chronic therapy implicating a multifactorial etiology in treatment response. Genetic studies implicate systemic immunity in AMD and systemic immune cells accumulate within CNV lesions, yet a role for these cells in anti-VEGF response remains undetermined. The purpose of this study was to identify transcriptional signatures of circulating immune cells that are associated with high anti-VEGF treatment burden. Design: Experimental pilot study. Participants: Patients with neovascular AMD seen at Washington University School of Medicine in St. Louis and BJC Health System. Methods: We profiled by single cell RNA sequencing the peripheral blood mononuclear cells of 27 treatment-experienced patients with wet AMD. We stratified this cohort into 2 groups with low and high treatment burden (≤ 5 or ≥ 6 injections in the past 12 months, respectively). Main Outcome Measures: Identification of immune cells associated with high treatment burden. Results: Gene expression signature of CD16+ monocytes may be associated with high treatment burden. Conclusions: These studies delineate potential signatures of circulating immune cells that may be associated with high treatment burden in neovascular AMD, potentially informing the development of diagnostic predictors of anti-VEGF response and new precision medicine-based approaches to complement anti-VEGF therapies. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Targeting cell-type-specific, choroid-peripheral immune signaling to treat age-related macular degeneration.

Age-related macular degeneration (AMD) is a leading cause of blindness featuring pathogenic neovascularization of the choroidal vasculature (CNV). Although systemic immunity plays a role in AMD, the ocular signals that recruit and activate immune cells remain poorly defined. Using single-cell RNA sequencing, we prospectively profile peripheral blood mononuclear cells from 65 individuals including AMD and controls, which we integrate with existing choroid data. We generate a network of choroid-peripheral immune interactions dysregulated in AMD, including known AMD-relevant gene vascular endothelial growth factor (VEGF) receptor 2. Additionally, we find CYR61 is upregulated in choroidal veins and may signal to circulating monocytes. In mice, we validate that CYR61 is abundant in endothelial cells within CNV lesions neighboring monocyte-derived macrophages. Mechanistically, CYR61 activates macrophage anti-angiogenic gene expression, and ocular Cyr61 knockdown increases murine CNV size, indicating CYR61 inhibits CNV. This study highlights the potential of multi-tissue human datasets to identify disease-relevant and potentially therapeutically modifiable targets.