Rescue of hearing and vestibular function in a mouse model of human deafness

Hearing impairment is the most common sensory disorder, with congenital hearing impairment present in ~1 in 1000 newborns(1), and yet there is no cellular cure for deafness. Hereditary deafness is often mediated by the developmental failure or degeneration of cochlear hair cells(2). Until now, it was not known whether such congenital failures could be mitigated by therapeutic intervention(3-5). 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 mutated USH1C.216G>A gene, which causes human Usher syndrome (Usher), the leading genetic cause of combined deafness and blindness(6,7). Treatment of neonatal mice with a single systemic dose of ASO partially corrects USH1C.216G>A splicing, increases protein expression, improves stereocilia organization in the cochlea, and rescues cochlear hair cells, vestibular function and hearing in mice. Our results demonstrate the therapeutic potential of ASOs in the treatment of deafness and provide evidence that congenital deafness can be effectively overcome by treatment early in development to correct gene expression.