Drug repurposing studies of PARP inhibitors as a new therapy for inherited retinal degeneration

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.

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Data availability

All data generated or analyzed during this study are included in this published article and its Supplementary Information file.

Abbreviations

ADPRT:

ADP-ribosyltransferase

ART:

ADP-ribosyltransferase

AIF:

Apoptosis-inducing factor

DAPI:

4′,6-diamidino-2-phenylindole

EDTA:

Ethylenediaminetetraacetic acid

GCL:

Ganglion cell layer

GSH:

Glutathion

GFAP:

Glial fibrillary acidic protein

GSK:

Glycogen synthase kinase

INL:

Inner nuclear layer

min:

Minutes

ODU:

Optical density units

ONL:

Outer nuclear layer

PDE6:

Phosphodiesterase-6

PARP:

Poly-ADP-ribose-polymerase

P:

Postnatal day

RP:

Retinitis pigmentosa

rd1:

Retinal degeneration 1

RPE:

Retinal pigment epithelium

SEM:

Standard error of the mean

s:

Seconds

TUNEL:

Terminal deoxynucleotidyl transferase dUTP nick end labeling

TMU:

N-(4-methoxybenzyl)-N′-(5-nitro-1,23-thiazol-2-yl)urea

wt:

Wild-type

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Acknowledgements

We thank Per Ekström, Eberhart Zrenner and Wadood Haq for scientific advice and discussions, and Sylvie Bolz and Christine Henes for excellent technical assistance. This work was supported by Deutsche Forschungsgemeinschaft (DFG; SA3040/1-1, DFG; SA3040/3-1), the Charlotte and Tistou Kerstan Foundation (SAH001/2016).

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AS carried out the in vitro retinal explant culture studies, and AS, NS, ES and JAFP carried out the analysis of immunohistology. SD and GK performed the studies on in silico drug analysis and MM carried out the analysis of GSH. MAA and DC performed GSK-alpha activity assay. AS conceived the study, AS, SD and MM participated in the design, analysis, coordination and interpretation of the study and drafted the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Ayse Sahaboglu or Serdar Durdagi.

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Sahaboglu, A., Miranda, M., Canjuga, D. et al. Drug repurposing studies of PARP inhibitors as a new therapy for inherited retinal degeneration. Cell. Mol. Life Sci. 77, 2199–2216 (2020). https://doi.org/10.1007/s00018-019-03283-2

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Keywords

  • Drug repurposing
  • PARP
  • Neuroprotection
  • Retinal degeneration
  • Molecular modeling