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

  • Ayse SahabogluEmail author
  • Maria Miranda
  • Denis Canjuga
  • Meltem Avci-Adali
  • Natalia Savytska
  • Enver Secer
  • Jessica Abigail Feria-Pliego
  • Gülru Kayık
  • Serdar DurdagiEmail author
Original Article

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

Drug repurposing PARP Neuroprotection Retinal degeneration Molecular modeling 

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

Notes

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).

Author contributions

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.

Compliance with ethical standards

Conflict of interest

The authors have declared that no conflict of interest exists.

Supplementary material

18_2019_3283_MOESM1_ESM.pdf (187 kb)
Supplementary material 1 (PDF 186 kb)
18_2019_3283_MOESM2_ESM.pdf (189 kb)
Supplementary material 2 (PDF 190 kb)
18_2019_3283_MOESM3_ESM.pdf (169 kb)
Supplementary material 3 (PDF 169 kb)

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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Division of Experimental OphthalmologyInstitute for Ophthalmic ResearchTübingenGermany
  2. 2.Computational Biology and Molecular Simulations Laboratory, Department of Biophysics, School of MedicineBahcesehir UniversityIstanbulTurkey
  3. 3.Departamento Ciencias BiomédicasUniversidad Cardenal Herrera-CEU UniversitiesValenciaSpain
  4. 4.Department of Thoracic and Cardiovascular SurgeryUniversity Hospital TübingenTübingenGermany
  5. 5.German Center for Neurodegenerative Diseases (DZNE)TübingenGermany
  6. 6.Universidad Nacional Autónoma de MéxicoCiudad de MéxicoMéxico
  7. 7.Department of Medical GeneticsErciyes UniversityKayseriTurkey

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