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@ARTICLE{Sahaboglu:145040,
author = {Sahaboglu, Ayse and Miranda, Maria and Canjuga, Denis and
Avci-Adali, Meltem and Savytska, Natalia and Secer, Enver
and Feria-Pliego, Jessica Abigail and Kayık, Gülru and
Durdagi, Serdar},
title = {{D}rug repurposing studies of {PARP} inhibitors as a new
therapy for inherited retinal degeneration.},
journal = {Cellular and molecular life sciences},
volume = {77},
number = {11},
issn = {1420-682X},
address = {Cham (ZG)},
publisher = {Springer International Publishing AG},
reportid = {DZNE-2020-00400},
pages = {2199-2216},
year = {2020},
abstract = {The enzyme poly-ADP-ribose-polymerase (PARP) has important
roles for many forms of DNA repair and it also participates
in transcription, chromatin remodeling and cell death
signaling. Currently, some PARP inhibitors are approved for
cancer therapy, by means of canceling DNA repair processes
and cell division. Drug repurposing is a new and attractive
aspect of therapy development that could offer low-cost 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 two different PARP
inhibitors, BMN-673 and 3-aminobenzamide, by using a
well-established retinitis pigmentosa model, the rd1 mouse.
Moreover, the mechanistic aspects of the PARP
inhibitor-induced protection were also investigated in the
present study. Our results showed that rd1 rod photoreceptor
cell death was decreased by about $25-40\%$ together with
the application of these two PARP inhibitors. The wealth of
human clinical data available for BMN-673 highlights a
strong potential for a rapid clinical translation into novel
retinitis pigmentosa treatments. Remarkably, we have found
that the efficacy of 3 aminobenzamide was able to decrease
PARylation at the nanomolar level. Our data also provide a
link between PARP activity with the Wnt/β-catenin pathway
and the major intracellular antioxidant concentrations
behind the PARP-dependent retinal degeneration. In addition,
molecular modeling studies were integrated with experimental
studies for better understanding of the role of PARP1
inhibitors in retinal degeneration.},
keywords = {Animals / Benzamides: therapeutic use / Drug Repositioning:
methods / Humans / Mice / Phthalazines: therapeutic use /
Poly(ADP-ribose) Polymerase Inhibitors: therapeutic use /
Poly(ADP-ribose) Polymerases: metabolism / Retina: drug
effects / Retina: metabolism / Retina: pathology / Retinal
Degeneration: drug therapy / Retinal Degeneration:
metabolism / Retinal Degeneration: pathology / Retinitis
Pigmentosa: drug therapy / Retinitis Pigmentosa: metabolism
/ Retinitis Pigmentosa: pathology / Benzamides (NLM
Chemicals) / Phthalazines (NLM Chemicals) / Poly(ADP-ribose)
Polymerase Inhibitors (NLM Chemicals) / 3-aminobenzamide
(NLM Chemicals) / talazoparib (NLM Chemicals) /
Poly(ADP-ribose) Polymerases (NLM Chemicals)},
cin = {AG Heutink},
ddc = {610},
cid = {I:(DE-2719)1210002},
pnm = {345 - Population Studies and Genetics (POF3-345)},
pid = {G:(DE-HGF)POF3-345},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:31451894},
doi = {10.1007/s00018-019-03283-2},
url = {https://pub.dzne.de/record/145040},
}