title: Attenuation of nonsense-mediated mRNA decay enhances in vivo nonsense suppression.
abstract: Nonsense suppression therapy is an approach to treat genetic diseases caused by nonsense mutations. This therapeutic strategy pharmacologically suppresses translation termination at Premature Termination Codons (PTCs) in order to restore expression of functional protein. However, the process of Nonsense-Mediated mRNA Decay (NMD), which reduces the abundance of mRNAs containing PTCs, frequently limits this approach. Here, we used a mouse model of the lysosomal storage disease mucopolysaccharidosis I-Hurler (MPS I-H) that carries a PTC in the Idua locus to test whether NMD attenuation can enhance PTC suppression in vivo. Idua encodes alpha-L-iduronidase, an enzyme required for degradation of the glycosaminoglycans (GAGs) heparan sulfate and dermatan sulfate. We found that the NMD attenuator NMDI-1 increased the abundance of the PTC-containing Idua transcript. Furthermore, co-administration of NMDI-1 with the PTC suppression drug gentamicin enhanced alpha-L-iduronidase activity compared to gentamicin alone, leading to a greater reduction of GAG storage in mouse tissues, including the brain. These results demonstrate that NMD attenuation significantly enhances suppression therapy in vivo.
authors.affiliation: Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America. kkeeling@uab.edu
authors.forename: Kim M
authors.initials: KM
authors.lastname: Keeling
authors.forename: Dan
authors.initials: D
authors.lastname: Wang
authors.forename: Yanying
authors.initials: Y
authors.lastname: Dai
authors.forename: Srinivasan
authors.initials: S
authors.lastname: Murugesan
authors.forename: Balachandra
authors.initials: B
authors.lastname: Chenna
authors.forename: Jeremy
authors.initials: J
authors.lastname: Clark
authors.forename: Valery
authors.initials: V
authors.lastname: Belakhov
authors.forename: Jeyakumar
authors.initials: J
authors.lastname: Kandasamy
authors.forename: Sadanandan E
authors.initials: SE
authors.lastname: Velu
authors.forename: Timor
authors.initials: T
authors.lastname: Baasov
authors.forename: David M
authors.initials: DM
authors.lastname: Bedwell
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D051379:Mice; D008059:Mucopolysaccharidosis I / Q000235:genetics; D059365:Nonsense Mediated mRNA Decay; D012333:RNA, Messenger / Q000235:genetics*
chemical_list: D012333:RNA, Messenger