1. Academic Validation
  2. Comprehensive Analysis of Combinatorial Pharmacological Treatments to Correct Nonsense Mutations in the CFTR Gene

Comprehensive Analysis of Combinatorial Pharmacological Treatments to Correct Nonsense Mutations in the CFTR Gene

  • Int J Mol Sci. 2021 Nov 4;22(21):11972. doi: 10.3390/ijms222111972.
Arianna Venturini 1 Anna Borrelli 1 Ilaria Musante 2 3 Paolo Scudieri 2 3 Valeria Capurro 2 Mario Renda 1 Nicoletta Pedemonte 2 Luis J V Galietta 1 4
Affiliations

Affiliations

  • 1 Telethon Institute of Genetics and Medicine (TIGEM), 80078 Pozzuoli, Italy.
  • 2 U.O.C. Genetica Medica, IRCCS Istituto Giannina Gaslini, 16147 Genova, Italy.
  • 3 Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), Università degli Studi di Genova, 16132 Genova, Italy.
  • 4 Department of Translational Medical Sciences (DISMET), Università degli Studi di Napoli "Federico II", 80131 Napoli, Italy.
Abstract

Cystic fibrosis (CF) is caused by loss of function of the CFTR Chloride Channel. A substantial number of CF patients carry nonsense mutations in the CFTR gene. These patients cannot directly benefit from pharmacological correctors and potentiators that have been developed for other types of CFTR mutations. We evaluated the efficacy of combinations of drugs targeting at various levels the effects of nonsense mutations: SMG1i to protect CFTR mRNA from nonsense-mediated decay (NMD), G418 and ELX-02 for readthrough, VX-809 and VX-445 to promote protein maturation and function, PTI-428 to enhance CFTR protein synthesis. We found that the extent of rescue and sensitivity to the various agents is largely dependent on the type of mutation, with W1282X and R553X being the mutations most and least sensitive to pharmacological treatments, respectively. In particular, W1282X-CFTR was highly responsive to NMD suppression by SMG1i but also required treatment with VX-445 corrector to show function. In contrast, G542X-CFTR required treatment with readthrough agents and VX-809. Importantly, we never found cooperativity between the NMD inhibitor and readthrough compounds. Our results indicate that treatment of CF patients with nonsense mutations requires a precision medicine approach with the design of specific drug combinations for each mutation.

Keywords

CFTR rescue; chloride channel; cystic fibrosis; nonsense mutation; readthrough therapy.

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