Towards personalized medicine in ophthalmology: a new therapeutic approach combining PARP-inhibition and AAV-mediated gene replacement improves vision in advanced stages of retinal neurodegeneration
Final Report Abstract
The combined therapeutic approach delineates a novel strategy for personalized treatment, necessitating a profound understanding and expertise in the major characteristics and key factors governing the distinctive pathological process associated with a particular mutation. This holds particular significance for Retinitis Pigmentosa (RP), a genetically diverse set of retinal hereditary conditions that lead to the death of photoreceptor cells, consequently leading to a gradual decreasing of the visual field and eventual total blindness. Despite the progressing understanding of genetics, there is currently no effective cure accessible for this condition in human patients. While the specific restoration of gene function appears to be an ideal therapeutic objective in genetic diseases, the genetic diversity and frequently delayed diagnosis of RP could pose a challenge for this particular approach in clinical ophthalmology practice. Drug repurposing is a new and attractive aspect of therapy development, that could offer lowcost and accelerated establishment of new treatment options. Excessive PARP activity is also involved in neurodegenerative diseases including the currently untreatable and blinding Retinitis Pigmentosa group of inherited retinal photoreceptor degenerations. Hence, repurposing of known PARP inhibitors for patients with non-oncological diseases might provide a facilitated route for a novel Retinitis Pigmentosa therapy. Here, we demonstrate and compare the efficacy of different PARP inhibitors by using a well-established Retinitis Pigmentosa models. Additionally, we investigated the mechanistic aspects underlying the protective effects induced by PARP inhibitors in the present research. Our findings indicate a reduction in rod photoreceptor cell death upon the application of PARP inhibitors. The extensive pool of clinical data available for PARP inhibitors utilized in this project holds strong potential for prompt clinical translation into new treatments for Retinitis Pigmentosa and conceivably other related retinal neurodegenerative conditions. Our data also provides a link between PARP activity with the Wnt/β-catenin pathway, GSH, extracellular vesicle, muller cell activity and the major intracellular antioxidant concentrations behind the PARP-dependent retinal degeneration.
Publications
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Drug repurposing studies of PARP inhibitors as a new therapy for inherited retinal degeneration. Cellular and Molecular Life Sciences, 77(11), 2199-2216.
Sahaboglu, Ayse; Miranda, Maria; Canjuga, Denis; Avci-Adali, Meltem; Savytska, Natalia; Secer, Enver; Feria-Pliego, Jessica Abigail; Kayık, Gülru & Durdagi, Serdar
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Poly ADP ribosylation and extracellular vesicle activity in rod photoreceptor degeneration. Scientific Reports, 9(1).
Vidal-Gil, Lorena; Sancho-Pelluz, Javier; Zrenner, Eberhart; Oltra, Maria & Sahaboglu, Ayse
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Release of Retinal Extracellular Vesicles in aModel of Retinitis Pigmentosa. Advances in Experimental Medicine and Biology, 431-436. Springer International Publishing.
Sahaboglu, Ayse; Vidal-Gil, Lorena & Sancho-Pelluz, Javier
