Repurposing of a PARP inhibitor for the experimental therapy of acute respiratory distress syndrome

• Grant number: 20/01381-1
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• Start date: May 01, 2022
• End date: April 30, 2023
• Field of knowledge: Health Sciences - Medicine
• Principal Investigator: Reinaldo Salomão
• Grantee: Sidneia Sousa Santos
• Supervisor: Csaba Szabo
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Institution abroad: Université de Fribourg, Switzerland
• Associated to the scholarship: 18/18418-5 - DNA repair, oxidative stress and metabolic dysfunction in sepsis - investigation of possible therapeutic target, BP.PD

Abstract

Poly(ADP-polymerase)1 (PARP1, the major isoform of a family of poly(ADP-ribosyl)ating enzymes), a constitutive enzyme, is a key regulator of DNA repair, cell death and gene expression. Activation of PARP in response to reactive oxidants promotes cell death and pro-inflammatory signalling. Pathophysiological PARP over-activation and the beneficial effects of PARP inhibitors have been demonstrated in various models of critical illness. However, a significant limitation of the field has been that no PARP inhibitors were available for human clinical studies. While in the 2000's many pharmaceutical companies launched their PARP inhibitor programs, these efforts focused on oncology indications because - independently from its roles in critical illness - PARP also plays a role in anticancer drug resistance. The first ultrapotent PARP inhibitor, olaparib, has been approved for ovarian cancer in 2015, with several additional PARP inhibitor approvals to follow. The clinical availability of PARP inhibitors opens the way for expanding the use of PARP inhibitors for non-oncological indications. Acute respiratory distress syndrome (ARDS) represents a prime indication for such repurposing efforts. The central hypothesis of the current project is that novel, clinically approved PARP inhibitors will be efficacious in protecting against cell dysfunction, hyper-inflammation and organ failure in preclinical models of ARDS. Using PARP inhibitor we will to compare the cytoprotective effect of the four clinically approved PARP inhibitors in vitro models of ARDS, to define the time-course and cell type specificity of PARP activation in clinical samples from patients with ARDS, and to evaluate the effect of the PARP inhibitor in cellular function, bioenergetics, and inflammatory mediator production in an ex vivo system utilizing patient-derived mononuclear cells. These studies may pave the way for the clinical introduction of a PARP inhibitor for experimental ARDS therapy. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

SANTOS, SIDNEIA SOUSA; RODRIGUES, LARISSA DE OLIVEIRA CAVALCANTI PERES; MARTINS, VANESSA; PETROSINO, MARIA; ZUHRA, KARIM; ASCENCAO, KELLY; ANAND, ABHISHEK; ABDEL-KADER, REHAM MAHMOUD; GAD, MOHAMED Z.; BOURQUIN, CAROLE; et al. Role of Cystathionine beta-Synthase and 3-Mercaptopyruvate Sulfurtransferase in the Regulation of Proliferation, Migration, and Bioenergetics of Murine Breast Cancer Cells. ANTIOXIDANTS, v. 12, n. 3, p. 17-pg., 2023-03-01. (20/01381-1)