Gli autori dello studio hanno testato un pannello di analoghi di inh-2, una molecola che agisce come inibitore della ligasi RNF5 (precedentemente identificata come 2A2). Essa interferisce sulla maturazione della proteina CFTR, attuando modifiche della molecola fondamentali per la sua attività. Hanno inoltre dimostrato che il recupero dell’attività di CFTR si osserva in cellule derivate da pazienti diversi. In aggiunta, è stato dimostrato che il trattamento cronico con inh-2 non determina effetti negativi sulle cellule bronchiali. Questi risultati dimostrano che l’inibizione di RNF5 determina un recupero di F508del-CFTR, non solo su modelli cellulari immortalizzati ma anche in epiteli bronchiali primari derivati da pazienti FC, confermando il ruolo di possibile nuovo bersaglio terapeutico di RNF5.
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.
– 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
