Investigating new therapeutic targets for inherited photoreceptor degeneration: Secondary medical indications for PARP inhibitors used in cancer treatment

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Inherited retinal degenerations (RD) such as Retinitis Pigmentosa are initiated by gene defects in rods, cones, or the retinal pigment epithelium and often lead to an irreversible loss in visual function. So far, there is no cure or treatment for RD. Poly-ADP-ribosylation (PARylation) is an important post-translational modification of proteins and is involved in many critical cellular pathways such as transcription, DNA repair, and programmed cell death. PARylation is performed by poly-ADP-ribose-polymerase (PARP) using NAD+ and antagonized by poly-ADP-ribose-glycohydrolase (PARG) which hydrolyses PAR polymers from acceptor proteins.In 2007, it was shown that over-activation of PARP contributed to photoreceptor degeneration in the rd1 mouse, a well-known model for RD. Since then, excessive PARP activity was also found to be involved in photoreceptor degeneration in a variety of further animal models for RD. This suggests PARP activity as a common denominator of photoreceptor cell death and, by inference, PARP inhibitors as therapeutic agents for inherited retinal diseases. Recently, several PARP inhibitors were clinically tested for the treatment of different types of cancer and the first PARP inhibitors have already been approved for use in cancer therapy.Here, I aim to investigate the therapeutic potential of clinically tested PARP inhibitors (Olaparib, BMN 673, INO-1001) using in vitro organotypic explant cultures derived from the rd1, rd2, and cpfl1 mouse models for RD. The identification of PARP inhibitors suitable for the treatment of RD would allow to build on the already existing extensive clinical data and fast-forward the translation of basic research into clinical application and new therapies for hereditary blindness.