Quantification of Ocular Gene Therapy-Related Inflammation Using the VRMACS Grading System.

Retinal gene therapy has been shown to be a benefit in treating inherited retinal degenerations and may become the first line of treatment for patients with more common conditions such as age-related macular degeneration and diabetic retinopathy. A major limitation of ocular gene therapy is inflammation which has occurred in several clinical trials and may be the cause of dose limiting toxicity. Up until now it is been difficult to grade inflammation due to the small number of studies across many different centers. The absence of a standardized, reproducible system to grade retinal inflammation limits cross-study comparisons and consistent safety assessment. We synthesize evidence from published retinal gene therapy studies that report inflammatory outcomes and from our gene therapy center. Based on these findings, we propose a standardized grading framework-the vitritis, retinitis, microperimetry changes, fundus autofluorescence abnormalities, choroiditis, and subretinal infiltrates (VRMACS) score-to assess retinal inflammation over time using clinical examination and multimodal imaging. The system evaluates 6 domains: vitritis, retinitis, microperimetry changes, fundus autofluorescence abnormalities, choroiditis, and subretinal infiltrates. Grading allows for structured, longitudinal assessment of inflammatory severity after gene therapy. The VRMACS score provides a standardized grading system that may improve detection, quantification, and reporting of inflammation associated with subretinal ocular gene therapy. Standardized inflammation grading could support dose selection, guide prespecified stopping rules, and improve consistency in the interpretation of inflammation-related adverse events across early- and late-phase trials. From a regulatory perspective, adoption of this system may support consistent safety assessment across clinical trials and facilitate regulatory evaluation of inflammation-related adverse events. Clinically, VRMACS offers a practical tool for monitoring patients receiving retinal gene therapy and guiding timely intervention.