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

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/ß-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.

Temporal progression of PARP activity in the Prph2 mutant rd2 mouse: Neuroprotective effects of the PARP inhibitor PJ34.

Peripherin (peripherin/rds) is a membrane-associated protein that plays a critical role in the morphogenesis of rod and cone photoreceptor outer segments. Mutations in the corresponding PRPH2 gene cause different types of retinal dystrophies characterized by a loss of photoreceptors. Over activation of poly-ADP-ribose polymerase (PARP) was previously shown to be involved in different animal models for hereditary retinal dystrophies. This includes the rd2 mouse, which suffers from a human homologous mutation in the PRPH2 gene. In the present study, we show that increased retinal PARP activity and poly-ADP-ribosylation of proteins occurs before the peak of rd2 photoreceptor degeneration. Inhibition of PARP activity with the well-characterized PARP inhibitor PJ34 decreased the levels of poly-ADP-ribosylation and photoreceptor cell death. These results suggest a causal involvement of PARP in photoreceptor degeneration caused by peripherin mutations and highlight the possibility to use PARP inhibition for the mutation-independent treatment of hereditary retinal dystrophies.

Olaparib significantly delays photoreceptor loss in a model for hereditary retinal degeneration.

The enzyme poly-ADP-ribose-polymerase (PARP) mediates DNA-repair and rearrangements of the nuclear chromatin. Generally, PARP activity is thought to promote cell survival and in recent years a number of PARP inhibitors have been clinically developed for cancer treatment. Paradoxically, PARP activity is also connected to many diseases including the untreatable blinding disease Retinitis Pigmentosa (RP), where PARP activity appears to drive the pathogenesis of photoreceptor loss. We tested the efficacy of three different PARP inhibitors to prevent photoreceptor loss in the rd1 mouse model for RP. In retinal explant cultures in vitro, olaparib had strong and long-lasting photoreceptor neuroprotective capacities. We demonstrated target engagement by showing that olaparib reduced photoreceptor accumulation of poly-ADP-ribosylated proteins. Remarkably, olaparib also reduced accumulation of cyclic-guanosine-monophosphate (cGMP), a characteristic marker for photoreceptor degeneration. Moreover, intravitreal injection of olaparib in rd1 animals diminished PARP activity and increased photoreceptor survival, confirming in vivo neuroprotection. This study affirms the role of PARP in inherited retinal degeneration and for the first time shows that a clinically approved PARP inhibitor can prevent photoreceptor degeneration in an RP model. The wealth of human clinical data available for olaparib highlights its strong potential for a rapid clinical translation into a novel RP treatment.