Clinical doses of amikacin provide more effective suppression of the human CFTR-G542X stop mutation than gentamicin in a transgenic CF mouse model.
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.
Department of Microbiology, The University of Alabama at Birmingham, 35294-2170, USA.
Ming
M
Du
Kim M
KM
Keeling
Liming
L
Fan
Xiaoli
X
Liu
Timea
T
Kovaçs
Eric
E
Sorscher
David M
DM
Bedwell
D000583:Amikacin / Q000097:blood / Q000494:pharmacology*; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D018389:Codon, Nonsense / Q000235:genetics*; D000242:Cyclic AMP / Q000494:pharmacology; D003550:Cystic Fibrosis / Q000235:genetics* / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D005839:Gentamicins / Q000097:blood / Q000494:pharmacology; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D014176:Protein Biosynthesis / Q000187:drug effects
D018389:Codon, Nonsense; D005839:Gentamicins; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D000583:Amikacin; D000242:Cyclic AMP