Retinal photoreceptor cilia and ciliopathies: Molecular mechanisms and therapeutic strategies

Abstract

Photoreceptor outer segments are specialized sensory cilia that are filled with flattened membranous discs responsible for transducing light into neural signals. These cilia maintain a dynamic system in which daily shedding of outer segments at distal tips balances continuous membrane synthesis, ensuring photoreceptor homeostasis. Mutations in ciliary genes impair the biogenesis or shedding of outer segments, leading to retinal ciliopathies. Recent studies have elucidated molecular mechanisms governing photoreceptor ciliary formation, maintenance, and renewal. In this review, we summarize current understanding of the spatiotemporal regulation of photoreceptor ciliogenesis and disc renewal, structural adaptations enabling light detection and protein trafficking, and pathogenic pathways from defective ciliary transport to photoreceptor degeneration. We further discuss emerging therapeutic strategies targeting cilia, including gene therapy and pharmacological intervention, as well as the potential application of targeted protein degradation and retinal organoid technologies, aimed at restoring ciliary function and photoreceptor viability.