Journal Article

DZNE-2020-00400

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Drug repurposing studies of PARP inhibitors as a new therapy for inherited retinal degeneration.

Sahaboglu, A. (Corresponding author) ; Miranda, M. ; Canjuga, D. ; Avci-Adali, M. ; Savytska, N.DZNE* ; Secer, E. ; Feria-Pliego, J. A. ; Kayık, G. ; Durdagi, S.

2020
Springer International Publishing AG Cham (ZG)

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Please use a persistent id in citations: doi:10.1007/s00018-019-03283-2

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.

Keyword(s): Animals (MeSH) ; Benzamides: therapeutic use (MeSH) ; Drug Repositioning: methods (MeSH) ; Humans (MeSH) ; Mice (MeSH) ; Phthalazines: therapeutic use (MeSH) ; Poly(ADP-ribose) Polymerase Inhibitors: therapeutic use (MeSH) ; Poly(ADP-ribose) Polymerases: metabolism (MeSH) ; Retina: drug effects (MeSH) ; Retina: metabolism (MeSH) ; Retina: pathology (MeSH) ; Retinal Degeneration: drug therapy (MeSH) ; Retinal Degeneration: metabolism (MeSH) ; Retinal Degeneration: pathology (MeSH) ; Retinitis Pigmentosa: drug therapy (MeSH) ; Retinitis Pigmentosa: metabolism (MeSH) ; Retinitis Pigmentosa: pathology (MeSH) ; Benzamides ; Phthalazines ; Poly(ADP-ribose) Polymerase Inhibitors ; 3-aminobenzamide ; talazoparib ; Poly(ADP-ribose) Polymerases

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Contributing Institute(s):

1. Genome Biology of Neurodegenerative Diseases (AG Heutink)

Research Program(s):

1. 345 - Population Studies and Genetics (POF3-345) (POF3-345)

Appears in the scientific report 2020

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Database coverage:
; BIOSIS Previews ; BIOSIS Reviews Reports And Meetings ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DEAL Springer ; Ebsco Academic Search ; Essential Science Indicators ; SCOPUS ; Web of Science Core Collection

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