Aminoglycosides can bypass nonsense mutations and are the prototypic agents for 
translational bypass therapy (TBT). Initial results demonstrate the need for 
more potent drugs and an in vivo model system for quantitative assessment of 
TBT. Herein, we present an in vivo system for evaluating the efficacy of 
premature stop codon management therapies: in vivo quantitative stop codon 
management repli-sampling TBT efficacy assay (IQSCMaRTEA). Application of 
IQSCMaRTEA reveals that geneticin is much more efficacious in vivo than 
gentamicin. Treatment with geneticin elicits a multiday response, and residual 
F9 antigen can be detected after 3 weeks. These data demonstrate the utility of 
IQSCMaRTEA for evaluating drugs that bypass nonsense mutations. In addition, 
IQSCMaRTEA may be helpful for testing inhibitors of nonsense-mediated decay, as 
stop codon management therapy will sometimes require inhibition of 
nonsense-mediated decay and translational bypass of the nonsense mutation. 
Furthermore, geneticin, its metabolites, or better tolerated analogues should be 
evaluated as a general treatment with multiday response for severe genetic 
disease caused by nonsense mutation.