A Mutation-Agnostic EP2–cAMP–Driven Strategy Restores Ciliogenesis and Retinal Function in Ciliopathies

Background: Defects in photoreceptor ciliary function cause retinal ciliopathies, a major group of inherited blinding disorders. Current therapies are limited by extensive genetic heterogeneity, small patient populations, and high development costs, underscoring the need for mutation-agnostic strategies. This study investigates cAMP signaling modulation as a means to enhance ciliogenesis and preserve retinal structure and function in models of retinal ciliopathies. Methods: Taprenepag, a selective prostaglandin E₂ EP2 receptor agonist, was characterized for receptor specificity and downstream signaling. Its ability to enhance ciliogenesis was assessed by immunofluorescence microscopy in patient-derived urine-derived renal epithelial cells (URECs) carrying NPHP1 or CEP290 mutations and in dermal fibroblasts from CEP290 , BBS1 , and BBS10 patients. In CEP290-deficient cells, which exhibited a spectrum of baseline ciliary defects, taprenepag’s effect on ciliogenesis was compared with forskolin and cAMP analogs. Intracellular cAMP levels were measured by ELISA to confirm EP2-mediated signaling. In vivo efficacy was evaluated in Cep290 -deficient mice following systemic taprenepag administration, with retinal morphology assessed by histology and function by electroretinography. Statistical significance was determined using one- or two-way ANOVA with appropriate post hoc tests. Results: Taprenepag significantly enhanced ciliogenesis across all mutant cell types through EP2-mediated cAMP elevation, effectively bypassing the need for gene-specific correction. In severely cilia-depleted cells, elevated cAMP alleviated early ciliogenesis defects, acting upstream of axoneme assembly and intraflagellar transport, suggesting that spatially restricted EP2 signaling initiates cilium formation. In Cep290 -deficient mice, taprenepag promoted photoreceptor outer segment development, increased outer nuclear layer thickness, and partially restored retinal responses, indicating both structural preservation and functional rescue. Conclusions: EP2 receptor activation and subsequent cAMP signaling constitute a mutation-independent mechanism to promote ciliogenesis and neuroprotection in retinal ciliopathies. Taprenepag demonstrates broad therapeutic potential across diverse genetic backgrounds, supporting cAMP modulation as a promising avenue for treating inherited retinal degeneration. These findings provide a foundation for the preclinical advancement of EP2 agonists as mutation-agnostic therapies for retinal ciliopathies.