Cell Death and Differentiation: A Novel Treatment of Cystic Fibrosis Acting On-Target

A novel treatment of cystic fibrosis acting on-target: cysteamine plus epigallocatechin gallate for the autophagy-dependent rescue of class II-mutated CFTR. Tosco A, De Gregorio F, Esposito S, De Stefano D, Sana I, Ferrari E, Sepe A, Salvadori L, Buonpensiero P, Di Pasqua A, Grassia R, Leone CA,Guido S, De Rosa G, Lusa S, Bona G, Stoll G, Maiuri MC, Mehta A, Kroemer G, Maiuri L, Raia V. Cell Death Differ. 2016 Aug;23(8):1380-93. doi: 10.1038/cdd.2016.22. Epub 2016 Apr 1. AbstractWe previously reported that the combination of two safe proteostasis regulators, cysteamine andepigallocatechin gallate (EGCG), can be used to improve deficient expression of the cystic fibrosistransmembrane conductance regulator (CFTR) in patients homozygous for the CFTR Phe508del mutation. Here we provide the proof-of-concept that this combination treatment restored CFTR function and reduced lung inflammation (P<0.001) in Phe508del/Phe508del or Phe508del/null-Cftr (but not in Cftr-null mice), provided that such mice were autophagy-competent. Primary nasal cells from patients bearing different class II CFTR mutations, either in homozygous or compound heterozygous form, responded to the treatment in vitro. We assessed individual responses to cysteamine plus EGCG in a single-centre, open-label phase-2 trial. The combination treatment decreased sweat chloride from baseline, increased both CFTR protein and function in …