title: Long-term nonsense suppression therapy moderates MPS I-H disease progression.
abstract: Nonsense suppression therapy is a therapeutic approach aimed at treating genetic diseases caused by in-frame premature termination codons (PTCs; also commonly known as nonsense mutations). This approach utilizes compounds that suppress translation termination at PTCs, which allows translation to continue and partial levels of deficient protein function to be restored. We hypothesize that suppression therapy can attenuate the lysosomal storage disease mucopolysaccharidosis type I-Hurler (MPS I-H), the severe form of α-L-iduronidase deficiency. α-L-iduronidase participates in glycosaminoglycan (GAG) catabolism and its insufficiency causes progressive GAG accumulation and onset of the MPS I-H phenotype, which consists of multiple somatic and neurological defects. 60-80% of MPS I-H patients carry a nonsense mutation in the IDUA gene. We previously showed that 2-week treatment with the designer aminoglycoside NB84 restored enough α-L-iduronidase function via PTC suppression to reduce tissue GAG accumulation in the Idua(tm1Kmke) MPS I-H mouse model, which carries a PTC homologous to the human IDUA-W402X nonsense mutation. Here we report that long-term NB84 administration maintains α-L-iduronidase activity and GAG reduction in Idua(tm1Kmke) mice throughout a 28-week treatment period. An examination of more complex MPS I-H phenotypes in Idua(tm1Kmke) mice following 28-week NB84 treatment revealed significant moderation of the disease in multiple tissues, including the brain, heart and bone, that are resistant to current MPS I-H therapies. This study represents the first demonstration that long-term nonsense suppression therapy can moderate progression of a genetic disease.
authors.affiliation: Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, USA. Electronic address: gwengunn@uab.edu.
authors.forename: Gwen
authors.initials: G
authors.lastname: Gunn
authors.affiliation: Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, USA. Electronic address: dyy@uab.edu.
authors.forename: Yanying
authors.initials: Y
authors.lastname: Dai
authors.affiliation: Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, USA. Electronic address: dalian@uab.edu.
authors.forename: Ming
authors.initials: M
authors.lastname: Du
authors.affiliation: The Edith and Joseph Enzyme Inhibitors Laboratory, Schulich Faculty of Chemistry, Technion-Israel Institute of Technology, Haifa, Israel. Electronic address: chvalery@tx.technion.ac.il.
authors.forename: Valery
authors.initials: V
authors.lastname: Belakhov
authors.affiliation: The Edith and Joseph Enzyme Inhibitors Laboratory, Schulich Faculty of Chemistry, Technion-Israel Institute of Technology, Haifa, Israel. Electronic address: jkumar@tx.technion.ac.il.
authors.forename: Jeyakumar
authors.initials: J
authors.lastname: Kandasamy
authors.affiliation: Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, USA. Electronic address: trs@uab.edu.
authors.forename: Trenton R
authors.initials: TR
authors.lastname: Schoeb
authors.affiliation: The Edith and Joseph Enzyme Inhibitors Laboratory, Schulich Faculty of Chemistry, Technion-Israel Institute of Technology, Haifa, Israel. Electronic address: chtimor@techunix.technion.ac.il.
authors.forename: Timor
authors.initials: T
authors.lastname: Baasov
authors.affiliation: Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, USA. Electronic address: dbedwell@uab.edu.
authors.forename: David M
authors.initials: DM
authors.lastname: Bedwell
authors.affiliation: Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, USA. Electronic address: kkeeling@uab.edu.
authors.forename: Kim M
authors.initials: KM
authors.lastname: Keeling
mesh_terms: D000617:Aminoglycosides / Q000008:administration & dosage*; D000818:Animals; D018389:Codon, Nonsense / Q000235:genetics*; D004195:Disease Models, Animal; D018450:Disease Progression; D006025:Glycosaminoglycans / Q000378:metabolism; D006801:Humans; D007068:Iduronidase / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008059:Mucopolysaccharidosis I / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics*; D010641:Phenotype; D014312:Trisaccharides / Q000008:administration & dosage*
chemical_list: D000617:Aminoglycosides; D018389:Codon, Nonsense; D006025:Glycosaminoglycans; D014312:Trisaccharides; C572445:aminoglycoside NB84; D007068:Iduronidase
keywords: Lysosomal storage disease; Mucopolysaccharidosis I-Hurler; Nonsense mutations; Nonsense suppression; Premature termination codons; Readthrough