Pigment Epithelium‐Derived Factor (PEDF)‐Based Therapy Induced Photoreceptor Survival by Stabilizing Choroidal Neovessels in a VEGF Overexpression CNV Rat Model

Pathological choroidal neovascularization (CNV), characterized by abnormal leaky vessel formation, can lead to vision impairment or blindness. Current standard treatment, anti‐vascular endothelial growth factor (VEGF) therapy, while effective, can be associated with severe local and systemic side effects and resistance in some patients, necessitating novel therapeutic approaches. Evidence from wet age‐related macular degeneration (AMD) donor eyes and patients suggests that functional, quiescent CNV can aid photoreceptor survival. Therefore, stabilizing functional neovessels rather than removing them could offer an effective alternative for treating pathological CNV. Pigment epithelium‐derived factor (PEDF), a multifunctional protein with antiangiogenic, neuroprotective, and vessel‐stabilizing properties, is a promising candidate for this approach. The efficacy of intravitreally injected PEDF protein, alone or in combination with bevacizumab, was investigated and compared to bevacizumab monotherapy in a VEGF overexpression‐induced CNV rat model using in vivo imaging and histology. Following PEDF + bevacizumab treatment, a significant reduction in CNV thickness was observed, comparable to bevacizumab monotherapy. Notably, only PEDF and PEDF + bevacizumab treatments significantly preserved retinal thickness and enhanced photoreceptor survival at the CNV site. Ultrastructural analysis revealed that PEDF and PEDF + bevacizumab treatments increased CNV vessel lumina, stabilized these vessels by reducing the thickness of the extracellular matrix and refining its structure, and enhanced vessel fenestration and pericyte coverage, making PEDF‐based therapy more effective than bevacizumab monotherapy. These findings suggest that supporting the maintenance of functional CNV vessels using PEDF may represent a novel and innovative strategy for the treatment of wet AMD.