Promoting readthrough of nonsense mutations in CF mouse model: Biodistribution and efficacy of NV848 in rescuing CFTR protein expression.

Autor:	Fiduccia I; Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, Palermo, Italy., Corrao F; Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, Palermo, Italy., Zizzo MG; Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, Palermo, Italy., Perriera R; Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, Palermo, Italy; Department of Research, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione), Via E. Tricomi 5, 90127 Palermo, Italy., Genovese F; Department of Diagnostic Laboratory, U.O.C. of Pathological Anatomy, 'G.F. Ingrassia' Hospital, ASP Palermo, Palermo, Italy., Vitale E; Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, Palermo, Italy., Ricci D; Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, Palermo, Italy., Melfi R; Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, Palermo, Italy., Tutone M; Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, Palermo, Italy., Pace A; Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, Palermo, Italy., Lentini L; Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, Palermo, Italy. Electronic address: laura.lentini@unipa.it., Pibiri I; Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, Palermo, Italy. Electronic address: ivana.pibiri@unipa.it.
Jazyk:	angličtina
Zdroj:	Molecular therapy : the journal of the American Society of Gene Therapy [Mol Ther] 2024 Dec 04; Vol. 32 (12), pp. 4514-4523. Date of Electronic Publication: 2024 Oct 28.
DOI:	10.1016/j.ymthe.2024.10.028
Abstrakt:	Nonsense mutations, often resulting from single-nucleotide substitutions, produce mRNA harboring a premature termination codon (PTC), which causes the premature termination of protein synthesis. This produces truncated and non-functional proteins, which cause different genetic diseases, including cystic fibrosis (CF). This work aims to investigate the ability of NV848 (N-(5-methyl-1,2,4-oxadiazol-3-yl)acetamide), a translational readthrough-inducing drug (TRID), to rescue CF transmembrane conductance regulator (CFTR) protein expression in a murine model characterized by the G542X nonsense mutation in the CFTR gene. In vitro experiments assessed the drug's stability in human hepatic metabolism, and in vivo investigations on wild-type mice allowed us to clarify the distribution of the drug to the target organs. Moreover, its efficacy in recovering the CFTR protein after chronic treatment was assessed in G542X homozygous mice. Our results provide valuable insights into the biodistribution and therapeutic attributes of NV848, representing a promising therapeutic tool for enhanced clinical outcomes in individuals affected by CF with nonsense mutations. Competing Interests: Declaration of interests I.P. is a scientific advisor of the CCM Bioscience group. I.P., L.L., A.P., M.T., and R.M. have patent licenses to WO2019101709. (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu