Related Experiment Video
Updated: Jun 9, 2025
Expression and Purification of the Cystic Fibrosis Transmembrane Conductance Regulator Protein in Saccharomyces cerevisiae
Published on: March 10, 2012
Promoting readthrough of nonsense mutations in CF mouse model: Biodistribution and efficacy of NV848 in rescuing CFTR
Ignazio Fiduccia1, Federica Corrao1, Maria Grazia Zizzo1
1Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, Palermo, Italy.
Abstract:
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.
Insights
Nonsense mutations cause genetic diseases like cystic fibrosis (CF) by creating premature stop codons. NV848, a readthrough drug, showed promise in restoring CF transmembrane conductance regulator (CFTR) protein in a CF mouse model.
Area of Science:
- Biochemistry
- Genetics
- Pharmacology
Background:
- Nonsense mutations lead to premature termination codons (PTC), resulting in truncated, non-functional proteins and genetic diseases such as cystic fibrosis (CF).
- Restoring functional protein expression is a key therapeutic strategy for genetic disorders caused by nonsense mutations.
Purpose of the Study:
- To evaluate NV848, a translational readthrough-inducing drug (TRID), for its efficacy in restoring CF transmembrane conductance regulator (CFTR) protein expression in a G542X nonsense mutation CF mouse model.
- To assess the pharmacokinetic and biodistribution properties of NV848.
Main Methods:
- In vitro stability assays in human hepatic metabolism.
- In vivo biodistribution studies in wild-type mice.
- Chronic treatment efficacy assessment in G542X homozygous CF mice to measure CFTR protein recovery.
Main Results:
- NV848 demonstrated stability in human hepatic metabolism.
- The drug successfully distributed to target organs in vivo.
- Chronic NV848 treatment led to the recovery of CFTR protein in G542X homozygous mice.
Conclusions:
- NV848 exhibits favorable biodistribution and therapeutic potential.
- This TRID represents a promising therapeutic candidate for treating CF caused by nonsense mutations.
- Further clinical investigation of NV848 for CF patients with nonsense mutations is warranted.
More Related Videos
08:37A Rapid and Facile Pipeline for Generating Genomic Point Mutants in C. elegans Using CRISPR/Cas9 Ribonucleoproteins
Published on: April 30, 2018
08:00Generation of Human Nasal Epithelial Cell Spheroids for Individualized Cystic Fibrosis Transmembrane Conductance Regulator Study
Published on: April 11, 2018
