June 2023
Volume 64, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2023
Neuroprotection based on a gene therapy approach for long-term expression of PEDF in retinitis pigmentosa mutant retinas
Author Affiliations & Notes
  • Valeria Marigo
    Department of Life Sciences, Universita degli Studi di Modena e Reggio Emilia, Modena, Emilia-Romagna, Italy
  • Andrea Bighinati
    Department of Life Sciences, Universita degli Studi di Modena e Reggio Emilia, Modena, Emilia-Romagna, Italy
  • Elisa Adani
    Department of Life Sciences, Universita degli Studi di Modena e Reggio Emilia, Modena, Emilia-Romagna, Italy
  • Maria Claudia Gargini
    Department of Pharmacy, Universita degli Studi di Pisa, Pisa, Toscana, Italy
  • Ilaria Piano
    Department of Pharmacy, Universita degli Studi di Pisa, Pisa, Toscana, Italy
  • S. Patricia Becerra
    National Eye Institute, Section of Protein Structure and Function, National Institutes of Health, Bethesda, Maryland, United States
  • Footnotes
    Commercial Relationships   Valeria Marigo None; Andrea Bighinati None; Elisa Adani None; Maria Claudia Gargini None; Ilaria Piano None; S. Patricia Becerra None
  • Footnotes
    Support  Fondazione Telethon GGP19113; JTC2020 TreatRP; PNNR CN3 “National Center for Gene Therapy and Drugs based on RNA Technology” Spoke 1
Investigative Ophthalmology & Visual Science June 2023, Vol.64, 3853. doi:
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      Valeria Marigo, Andrea Bighinati, Elisa Adani, Maria Claudia Gargini, Ilaria Piano, S. Patricia Becerra; Neuroprotection based on a gene therapy approach for long-term expression of PEDF in retinitis pigmentosa mutant retinas. Invest. Ophthalmol. Vis. Sci. 2023;64(8):3853.

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      © ARVO (1962-2015); The Authors (2016-present)

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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.

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