H105A peptide eye drops promote photoreceptor survival in murine and human models of retinal degeneration

Abstract Background Photoreceptor death leads to inherited blinding retinal diseases, such as retinitis pigmentosa (RP). As disease progression often outpaces therapeutic advances, developing effective treatments is urgent. This study evaluates the efficacy of small peptides derived from pigment epithelium-derived factor (PEDF), which are known to restrict common cell death pathways associated with retinal diseases. Methods We tested chemically synthesized peptides (17-mer and H105A) with affinity for the PEDF receptor, PEDF-R, delivered as eye drops to two RP mouse models: rd10 (phosphodiesterase 6b mutation) and Rho P23H/+ (rhodopsin P23H mutation). Additionally, we engineered AAV-H105A vectors for intravitreal delivery in Rho P23H/+ mice. To assess peptide effects in human tissue, we used retinal organoids exposed to cigarette smoke extract, a model of oxidative stress. Photoreceptor survival, morphology and function were evaluated. Results Here we show that peptides 17-mer and H105A delivered via eye drops successfully reach the retina, promote photoreceptor survival, and improve retinal function in both RP mouse models. Intravitreal delivery of a AAV-H105A vector delays photoreceptor degeneration in Rho P23H/+ mice up to six months. In human retinal organoids, peptide H105A specifically prevents photoreceptor death induced by oxidative stress, a contributing factor to RP progression. Conclusions PEDF peptide-based eye drops offer a promising, minimally invasive therapy to prevent photoreceptor degeneration in retinal disorders, with a favorable safety profile.