Abstract
Purpose :
Inherited Retinal Degenerations (IRD), like Retinitis Pigmentosa (RP), are characterized by a progressive loss of visual acuity caused by degeneration of photoreceptor cells. The main issue with IRDs is their huge heterogeneity in both symptoms and genetics. RP could arise from mutations in hundreds of genes and the phenotype of the disease is highly variable. Due to this high heterogeneity, therapeutic approaches targeting specific genes can benefit a limited number of patients, while few or no medical options are available for most forms of RP. Based on the slow progression of the diseases, a possible therapeutic option is to delay photoreceptor degeneration and in turn progression of the disease. We previously demonstrated that administration of Pigment Epithelium-derived Factor (PEDF), a neurotrophic factor of the retina, or its derived peptide 17-mer[H105A], that we previously characterized, delays retinal degeneration in several models of RP. The aim of this study is the development of a sustained expression for PEDF or PEDF-derived peptide based on a gene therapy approach.
Methods :
PEDF or 17-mer[H105A] were intravitreally delivered to the retina of RHO-P23H knock-in mice by AAV. Expression of the transduced constructs was analyzed by Real-time qPCR and western blotting at 1 and 3 months after viral injection. Cell death and inflammation were followed by TUNEL assay and Iba1 staining, respectively, 14 days after injection. Retinal function was assessed by ERG at 6 months after viral injection.
Results :
We visualized PEDF in retinal sections at 14 days post-injection and detected transduction mainly in retinal ganglion cells and Müller glia cells. PEDF expression was detected at mRNA and protein levels in transduced retinas at 1 and 3 months after viral injection. A significant decrease of cell death and inflammation was found in retinas expressing either PEDF or 17-mer[H105A] when compared to control EGFP expressing retinas.
Conclusions :
Transduction of AAV-PEDF was observed in RGCs and Müller cells that decreased cell death and inflammation in the retinas. Our findings highlight an early neuroprotective and immunoregulatory effect of PEDF and 17-mer[H105A], and their roles as potential therapeutic agents for IRDs.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.