Synthetic aminoglycosides efficiently suppress cystic fibrosis transmembrane conductance regulator nonsense mutations and are enhanced by ivacaftor

Am J Respir Cell Mol Biol. 2014 Apr;50(4):805-16. doi: 10.1165/rcmb.2013-0282OC.


New drugs are needed to enhance premature termination codon (PTC) suppression to treat the underlying cause of cystic fibrosis (CF) and other diseases caused by nonsense mutations. We tested new synthetic aminoglycoside derivatives expressly developed for PTC suppression in a series of complementary CF models. Using a dual-luciferase reporter system containing the four most prevalent CF transmembrane conductance regulator (CFTR) nonsense mutations (G542X, R553X, R1162X, and W1282X) within their local sequence contexts (the three codons on either side of the PTC), we found that NB124 promoted the most readthrough of G542X, R1162X, and W1282X PTCs. NB124 also restored full-length CFTR expression and chloride transport in Fischer rat thyroid cells stably transduced with a CFTR-G542XcDNA transgene, and was superior to gentamicin and other aminoglycosides tested. NB124 restored CFTR function to roughly 7% of wild-type activity in primary human bronchial epithelial (HBE) CF cells (G542X/delF508), a highly relevant preclinical model with endogenous CFTR expression. Efficacy was further enhanced by addition of the CFTR potentiator, ivacaftor (VX-770), to airway cells expressing CFTR PTCs. NB124 treatment rescued CFTR function in a CF mouse model expressing a human CFTR-G542X transgene; efficacy was superior to gentamicin and exhibited favorable pharmacokinetic properties, suggesting that in vitro results translated to clinical benefit in vivo. NB124 was also less cytotoxic than gentamicin in a tissue-based model for ototoxicity. These results provide evidence that NB124 and other synthetic aminoglycosides provide a 10-fold improvement in therapeutic index over gentamicin and other first-generation aminoglycosides, providing a promising treatment for a wide array of CFTR nonsense mutations.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminoglycosides / chemical synthesis
  • Aminoglycosides / pharmacokinetics
  • Aminoglycosides / pharmacology*
  • Aminoglycosides / toxicity
  • Aminophenols / pharmacokinetics
  • Aminophenols / pharmacology*
  • Animals
  • Biological Transport
  • Cell Line
  • Chlorides / metabolism
  • Codon, Nonsense / drug effects*
  • Cystic Fibrosis / drug therapy*
  • Cystic Fibrosis / genetics
  • Cystic Fibrosis / metabolism
  • Cystic Fibrosis Transmembrane Conductance Regulator / drug effects*
  • Cystic Fibrosis Transmembrane Conductance Regulator / genetics
  • Cystic Fibrosis Transmembrane Conductance Regulator / metabolism
  • Disease Models, Animal
  • Drug Synergism
  • Genes, Reporter
  • Humans
  • Luciferases / genetics
  • Luciferases / metabolism
  • Mice
  • Mice, Inbred CFTR
  • Mice, Transgenic
  • Organ of Corti / drug effects
  • Organ of Corti / pathology
  • Quinolones / pharmacokinetics
  • Quinolones / pharmacology*
  • Rats
  • Rats, Inbred F344
  • Time Factors
  • Transfection


  • 5-O-(5-amino-5-deoxyribofuranosyl)-1N-(4-amino-2-hydroxybutanoyl)paromamine
  • Aminoglycosides
  • Aminophenols
  • CFTR protein, human
  • Chlorides
  • Codon, Nonsense
  • Quinolones
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • ivacaftor
  • Luciferases