Pharmacological cAMP stimulation via prostaglandin receptors rescues ciliary defects in CEP290-deficient human and mouse models

ABSTRACT The retina’s sensitivity to light depends on the primary cilium of photoreceptors, known as the outer segment (OS). OS defects are a primary cause of inherited retinal dystrophies (IRDs) and can also indicate wider ciliary dysfunctions. One such IRD is Leber congenital amaurosis type 10 (LCA10), which occurs as a monosymptomatic retinal disease or the presenting symptom of syndromic ciliopathies within the Senior-Loken-Joubert-Meckel spectrum. LCA10 patients are born blind but retain dormant photoreceptors for decades, offering the potential for reactivation. AAV-based gene therapies for IRDs cannot accommodate the large CEP290 gene, prompting the search for innovative treatments. LCA10 is caused by mutations in CEP290 , which plays a vital role in ciliation, similar to cAMP signaling. Utilizing fibroblasts displaying variable CEP290 mutations and associated ciliary defects, we show that exposure to Taprenepag, a specific PGE2 receptor agonist, substantially stimulated cAMP synthesis and consistently improved cilia formation and elongation. We also found that intraperitoneal injection of Taprenepag in mice reached the retina and slowed retinal degeneration, promoting OS formation, and improving light sensitivity in a Cep290 mutant mouse. These findings demonstrate the potential of Taprenepag to treat the CEP290-related visual dysfunction and suggest evaluation for other CEP290-related organ issues and ciliopathies.