Periodic Reporting for period 1 - SENFIB (Novel senolytic drugs for the treatment of lung and kidney fibrosis)
Reporting period: 2021-05-01 to 2022-10-31
Senescent cells are cells that have experienced damage, yet remain persistent and long-lived within their resident tissue, generating a persistent, sterile inflammation. Research has found that senescent cells are associated with and causative in a wide range of diseases, including fibrotic diseases. Fundamentally, these diseases are internal scarring processes that result in inappropriate matrix deposition and deterioration of tissue function, ultimately leading to organ failure. Fibrotic diseases are estimated to account for up to 45% of all-cause mortality in the developed world, yet no treatments exist for their effective management. Research has shown that reducing the senescent cell burden in fibrotic disease models can alleviate disease phenotypes. “Senolytics” is the general term given to molecules that induce the selective killing of senescent cells while leaving healthy cells intact; senolytics have the potential to stop and even reverse the disease burden of fibrotic pathologies according to preclinical data. However, few senolytic molecules have been identified; of the few identified, some have unknown mechanisms of action, some present serious toxicities, and most importantly, none has yet been demonstrated to have therapeutic activity in clinical trials. The goal of SENFIB was to develop a novel small molecule inhibitor drug with senolytic properties for the treatment of fibrotic diseases. Through the ERC PoC SENFIB project, we have rationally designed, synthesized, and tested a series of potential senolytic therapeutics. We have identified one “best” potential candidate based on its senolytic activity, and we are currently developing it for in vivo formulation. Pilot experiments in mouse models indicate our compound has in vivo senolytic activity, and we are currently testing its efficacy in reducing disease burden in a variety of fibrotic diseases. Thanks to the knowledge generated through the ERC PoC, we have also identified several other genes whose inhibition leads to senolysis. In the future, our goal is to bring compounds developed through the ERC PoC into clinical phases, to help ease disease burden for patients suffering from fibrotic diseases, as well as ease the economic burdens of currently incurable end-stage diseases.