The authors tested a set of inh-2 analogs and identified moieties that are mandatory for the activity of the compounds. They verified the ability of inh-2 to rescue F508del-CFTR on well-differentiated primary cultures of human bronchial epithelial cells from various F508del homozygous subjects and observed a lack of side effects after long-term treatment of bronchial cells with inh-2. It was also demonstrated that inh-2 is additive with both C2 and C3 types of correctors. These results clearly demonstrate that RNF5 inhibition can rescue F508del-CFTR trafficking defect and that this mechanism is not only amenable in cell lines or in a murine CF model, but also in human primary bronchial epithelia, that are the main target tissue of CF treatment. These findings thus validate RNF5 as a drug target for CF and provide evidence to support its druggability.

Congress abstracts

– Tomati V, Sondo E, Pesce E et al. “Novel regulators of F508del-CFTR identified by means of a functional genomics approach in human bronchial epithelial cells: possible mechanisms of action” North American Cystic Fibrosis Conference (NACF), October 18-20, 2018, Denver, CO, USA
– Pedemonte N. “Therapeutic potential of proteostasis modulation in cystic fibrosis” 14th ECFS Basic Science Conference, 29 March – 1 April 2017,Albufeira, Portugal