title: Rescue of hearing and vestibular function by antisense oligonucleotides in a mouse model of human deafness.
abstract: Hearing impairment is the most common sensory disorder, with congenital hearing impairment present in approximately 1 in 1,000 newborns. Hereditary deafness is often mediated by the improper development or degeneration of cochlear hair cells. Until now, it was not known whether such congenital failures could be mitigated by therapeutic intervention. Here we show that hearing and vestibular function can be rescued in a mouse model of human hereditary deafness. An antisense oligonucleotide (ASO) was used to correct defective pre-mRNA splicing of transcripts from the USH1C gene with the c.216G>A mutation, which causes human Usher syndrome, the leading genetic cause of combined deafness and blindness. Treatment of neonatal mice with a single systemic dose of ASO partially corrects Ush1c c.216G>A splicing, increases protein expression, improves stereocilia organization in the cochlea, and rescues cochlear hair cells, vestibular function and low-frequency hearing in mice. These effects were sustained for several months, providing evidence that congenital deafness can be effectively overcome by treatment early in development to correct gene expression and demonstrating the therapeutic potential of ASOs in the treatment of deafness.
authors: Neuroscience Center and Department of Otorhinolaryngology & Biocommunications, Louisiana State University Health Sciences Center (LSUHSC), New Orleans, Louisiana, USA. jlentz@lsuhsc.edu
authors: Jennifer J
authors: JJ
authors: Lentz
authors: Francine M
authors: FM
authors: Jodelka
authors: Anthony J
authors: AJ
authors: Hinrich
authors: Kate E
authors: KE
authors: McCaffrey
authors: Hamilton E
authors: HE
authors: Farris
authors: Matthew J
authors: MJ
authors: Spalitta
authors: Nicolas G
authors: NG
authors: Bazan
authors: Dominik M
authors: DM
authors: Duelli
authors: Frank
authors: F
authors: Rigo
authors: Michelle L
authors: ML
authors: Hastings
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics*; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D003051:Cochlea / Q000378:metabolism; D003598:Cytoskeletal Proteins; D004195:Disease Models, Animal; D016057:Evoked Potentials, Auditory, Brain Stem; D015316:Genetic Therapy; D006198:Hair Cells, Auditory / Q000378:metabolism; D006367:HeLa Cells; D006309:Hearing; D006801:Humans; D051379:Mice; D016376:Oligonucleotides, Antisense / Q000627:therapeutic use*; D059547:Stereocilia / Q000235:genetics; D052245:Usher Syndromes / Q000235:genetics* / Q000378:metabolism / Q000628:therapy*; D014722:Vestibule, Labyrinth / Q000502:physiology
chemical_list: D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; D016376:Oligonucleotides, Antisense; C492262:Ush1c protein, mouse
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