title: A mouse model for nonsense mutation bypass therapy shows a dramatic multiday response to geneticin.
abstract: 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.
authors: Department of Molecular Genetics, City of Hope National Medical Center, Duarte, CA 91010, USA.
authors: Chunmei
authors: C
authors: Yang
authors: Jinong
authors: J
authors: Feng
authors: Wenjia
authors: W
authors: Song
authors: Jicheng
authors: J
authors: Wang
authors: Becky
authors: B
authors: Tsai
authors: Yunwu
authors: Y
authors: Zhang
authors: William A
authors: WA
authors: Scaringe
authors: Kathleen A
authors: KA
authors: Hill
authors: Paris
authors: P
authors: Margaritis
authors: Katherine A
authors: KA
authors: High
authors: Steve S
authors: SS
authors: Sommer
mesh_terms: D000563:Amebicides / Q000494:pharmacology*; D000617:Aminoglycosides / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D018389:Codon, Nonsense; D018388:Codon, Terminator / Q000378:metabolism; D004195:Disease Models, Animal; D005839:Gentamicins / Q000494:pharmacology*; D006467:Hemophilia A / Q000235:genetics / Q000628:therapy; D006801:Humans; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008957:Models, Genetic; D014176:Protein Biosynthesis
chemical_list: D000563:Amebicides; D000617:Aminoglycosides; D000970:Antineoplastic Agents; D018389:Codon, Nonsense; D018388:Codon, Terminator; D005839:Gentamicins; C010680:antibiotic G 418