Repurposing of a clinically used poly(ADP-ribose) polymerase inhibitor for the experimental therapy of ARDS

Poly(ADP-polymerase)1 (PARP1, the major isoform of a family of poly(ADP-ribosyl)ating enzymes), a constitutive nuclear and mitochondrial enzyme, is a key regulator of DNA repair, cell death and gene expression. Activation of PARP1 in response to reactive oxidants / free radicals promotes cell death and pro-inflammatory signaling in various forms of critical illness. Recently, PARP1 activation was demonstrated in various forms of human disease (including various forms of critical illness). A significant limitation of the field has been that no potent or specific PARP inhibitors were available for clinical or translational efficacy studies. While in the 2000's many pharmaceutical companies launched their PARP inhibitor programs, these efforts focused exclusively on oncology indications (independently from its role in critical illness, PARP also plays a role in cancer cell DNA repair and anticancer drug resistance). The first ultrapotent PARP inhibitor, olaparib, has been approved for the therapy of ovarian cancer in 2015 by the EMEA and the FDA, with several other PARP inhibitors more recently approved or in late-stage clinical trials. The clinical availability of olaparib opens the way for expanding the clinical use of PARP inhibitors for non-oncological indications. As outlined in our recent position paper, acute respiratory distress syndrome (ARDS) represents a prime indication for such repurposing' efforts, as it is supported by preclinical data with earlier generation PARP inhibitors and by recent data with olaparib in various preclinical models of critical illness. We hypothesize that novel, clinically approved PARP inhibitors will be efficacious in protecting against cell dysfunction, hyper-inflammation and organ failure in preclinical models of ARDS. We also expect that - after comparing the efficacy and safety of all 4 clinically approved PARP inhibitors - we will be able to identify one single PARP inhibitor that will exhibit the best efficacy/safety profile. This inhibitor will, in turn, progress into follow-up efficacy and safety studies. The data generated in the current project are essential to support subsequent clinical testing of a clinically approved, repurposable PARP inhibitor for the therapy of patients suffering from ARDS.