Olaparib significantly delays photoreceptor loss in a model for hereditary retinal degeneration

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Sahaboglu , A , Barth , M , Secer , E , del Amo , E M , Urtti , A , Arsenijevic , Y , Zrenner , E & Paquet-Durand , F 2016 , ' Olaparib significantly delays photoreceptor loss in a model for hereditary retinal degeneration ' , Scientific Reports , vol. 6 , 39537 . https://doi.org/10.1038/srep39537

Title: Olaparib significantly delays photoreceptor loss in a model for hereditary retinal degeneration
Author: Sahaboglu, Ayse; Barth, Melanie; Secer, Enver; del Amo, Eva M.; Urtti, Arto; Arsenijevic, Yvan; Zrenner, Eberhart; Paquet-Durand, Francois
Contributor: University of Helsinki, Faculty of Pharmacy
Date: 2016-12-22
Language: eng
Number of pages: 11
Belongs to series: Scientific Reports
ISSN: 2045-2322
URI: http://hdl.handle.net/10138/173313
Abstract: The enzyme poly-ADP-ribose-polymerase (PARP) mediates DNA-repair and rearrangements of the nuclear chromatin. Generally, PARP activity is thought to promote cell survival and in recent years a number of PARP inhibitors have been clinically developed for cancer treatment. Paradoxically, PARP activity is also connected to many diseases including the untreatable blinding disease Retinitis Pigmentosa (RP), where PARP activity appears to drive the pathogenesis of photoreceptor loss. We tested the efficacy of three different PARP inhibitors to prevent photoreceptor loss in the rd1 mouse model for RP. In retinal explant cultures in vitro, olaparib had strong and long-lasting photoreceptor neuroprotective capacities. We demonstrated target engagement by showing that olaparib reduced photoreceptor accumulation of poly-ADP-ribosylated proteins. Remarkably, olaparib also reduced accumulation of cyclic-guanosine-monophosphate (cGMP), a characteristic marker for photoreceptor degeneration. Moreover, intravitreal injection of olaparib in rd1 animals diminished PARP activity and increased photoreceptor survival, confirming in vivo neuroprotection. This study affirms the role of PARP in inherited retinal degeneration and for the first time shows that a clinically approved PARP inhibitor can prevent photoreceptor degeneration in an RP model. The wealth of human clinical data available for olaparib highlights its strong potential for a rapid clinical translation into a novel RP treatment.
Subject: ROD CGMP-PHOSPHODIESTERASE
MOUSE RETINA
DNA-DAMAGE
CELL-DEATH
POLY(ADP-RIBOSE) POLYMERASE
THERAPEUTIC OPPORTUNITIES
PARP INHIBITORS
BETA-SUBUNIT
ACTIVATION
PIGMENTOSA
3112 Neurosciences
1184 Genetics, developmental biology, physiology
317 Pharmacy
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