title: Olaparib significantly delays photoreceptor loss in a model for hereditary retinal degeneration.
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.
authors.affiliation: Institute for Ophthalmic Research, Tuebingen, Germany.
authors.forename: Ayse
authors.initials: A
authors.lastname: Sahaboglu
authors.affiliation: Institute for Ophthalmic Research, Tuebingen, Germany.|Graduate Training Center of Neuroscience, Tuebingen, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Barth
authors.affiliation: Institute for Ophthalmic Research, Tuebingen, Germany.|Department of Medical Genetics, Erciyes University, Kayseri, Turkey.
authors.forename: Enver
authors.initials: E
authors.lastname: Secer
authors.affiliation: School of Pharmacy, University of Eastern Finland, Kuopio, Finland.
authors.forename: Eva M Del
authors.initials: EM
authors.lastname: Amo
authors.affiliation: School of Pharmacy, University of Eastern Finland, Kuopio, Finland.|Centre for Drug Research, Division of Pharmaceutical Biosciences, University of Helsinki, Helsinki, Finland.
authors.forename: Arto
authors.initials: A
authors.lastname: Urtti
authors.affiliation: Hôpital Ophtalmique Jules Gonin, Lausanne, Switzerland.
authors.forename: Yvan
authors.initials: Y
authors.lastname: Arsenijevic
authors.affiliation: Institute for Ophthalmic Research, Tuebingen, Germany.
authors.forename: Eberhart
authors.initials: E
authors.lastname: Zrenner
authors.affiliation: Institute for Ophthalmic Research, Tuebingen, Germany.
authors.forename: François
authors.initials: F
authors.lastname: Paquet-Durand
mesh_terms: D000818:Animals; D002470:Cell Survival; D002843:Chromatin / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D007150:Immunohistochemistry; D051379:Mice; D008809:Mice, Inbred C3H; D009369:Neoplasms / Q000188:drug therapy; D018696:Neuroprotective Agents / Q000494:pharmacology*; D020419:Photoreceptor Cells, Vertebrate / Q000187:drug effects*; D010793:Phthalazines / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D011817:Rabbits; D012162:Retinal Degeneration / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology
chemical_list: D002843:Chromatin; D018696:Neuroprotective Agents; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases; D006152:Cyclic GMP; C531550:olaparib