Journal of Molecular Medicine

, Volume 84, Issue 7, pp 573–582

Clinical doses of amikacin provide more effective suppression of the human CFTR-G542X stop mutation than gentamicin in a transgenic CF mouse model

  • Ming Du
  • Kim M. Keeling
  • Liming Fan
  • Xiaoli Liu
  • Timea Kovaçs
  • Eric Sorscher
  • David M. Bedwell
Original Article

DOI: 10.1007/s00109-006-0045-5

Cite this article as:
Du, M., Keeling, K.M., Fan, L. et al. J Mol Med (2006) 84: 573. doi:10.1007/s00109-006-0045-5

Abstract

Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene cause the disease cystic fibrosis. We previously reported that gentamicin administration suppressed a CFTR premature stop mutation in a Cftr−/− mouse model carrying a human CFTR-G542X (hCFTR-G542X) transgene, resulting in the appearance of hCFTR protein and function. However, the high doses used in that study resulted in peak serum levels well beyond the levels typically administered to humans. To address this problem, we identified doses of both gentamicin and amikacin that resulted in peak serum levels within their accepted clinical ranges. We then asked whether these doses could suppress the hCFTR-G542X mutation in the Cftr−/− hCFTR-G542X mouse model. Our results indicate that low doses of each compound restored some hCFTR protein expression and function, as shown by immunofluorescence and short-circuit current measurements. However, we found that amikacin suppressed the hCFTR-G542X premature stop mutation more effectively than gentamicin when administered at these clinically relevant doses. Because amikacin is also less toxic than gentamicin, it may represent a superior choice for suppression therapy in patients that carry a premature stop mutation in the CFTR gene.

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Ming Du
    • 1
    • 3
  • Kim M. Keeling
    • 1
    • 3
  • Liming Fan
    • 1
    • 3
  • Xiaoli Liu
    • 1
    • 3
  • Timea Kovaçs
    • 2
    • 3
  • Eric Sorscher
    • 2
    • 3
  • David M. Bedwell
    • 1
    • 3
  1. 1.Department of MicrobiologyThe University of Alabama at BirminghamBirminghamUSA
  2. 2.Department of Physiology and BiophysicsUniversity of Alabama at BirminghamBirminghamUSA
  3. 3.Gregory Fleming James Cystic Fibrosis Research CenterUniversity of Alabama at BirminghamBirminghamUSA