Keeping the lights on: a new role for an old drug to support cone survival in Retinitis Pigmentosa

Abstract

Retinitis Pigmentosa (RP) is an incurable disorder characterized by progressive vision loss due to photoreceptor degeneration, typically following a rod-cone sequence. Rods die first, driven by primary genetic mutations; cones then degenerate secondarily through bystander mechanisms. As cones mediate daylight and high-acuity vision, crucial to human visual function, even partial preservation of these cells can profoundly enhance quality of life, regardless of the underlying genetic defect. Although significant progress has been made in understanding RP genetics and developing targeted therapies such as gene augmentation, a universal cure remains out of reach. This review centers on the biological drivers of secondary cone degeneration, with a focus on oxidative stress, metabolic dysfunction, and inflammation. Inflammation, now recognized as a key contributor to RP progression, involves the activation of microglia and infiltration by macrophages, both of which exacerbate retinal damage and offer promising therapeutic targets. We briefly survey current treatment modalities that have advanced to clinical application, including gene therapies, retinal prostheses, and neuroprotective strategies. Building on this therapeutic landscape, we propose a rationale for exploring ocular glucocorticoids-specifically dexamethasone-as a treatment avenue. Recent in vivo evidence from the rd10 mouse model demonstrates that intraocular dexamethasone, a long-approved agent for ocular inflammation, can preserve cone photoreceptors and protect the retinal pigment epithelium, a critical barrier for retinal homeostasis. Glucocorticoids may thus represent a class of mutation-agnostic therapeutics with strong translational promise. Their repurposing for RP could help safeguard photoreceptors and visual function, addressing a pressing and unmet clinical need.