Hearing impairment is the most common sensory disorder, with congenital hearing impairment present in approximately 1 in 1,000 newborns 1 . Hereditary deafness is often mediated by the improper development or degeneration of cochlear hair cells 2 . Until now, it was not known whether such congenital failures could be mitigated by therapeutic intervention 3, 4, 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 USH1C gene with the c.216G>A mutation, which causes human Usher syndrome, 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 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.
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We gratefully acknowledge support from the Hearing Health Foundation, Midwest Eye-Banks, the National Organization for Hearing Research Foundation, Capita Foundation and the US National Institutes of Health. We thank D. Cunningham and E. Rubel for assistance with scanning electron microscopy analysis; A. Rosenkranz, R. Marr and M. Oblinger for use of equipment; J. Huang for assistance with open-field analysis, L. Ochoa for assistance with ABR analysis computer support, G. MacDonald for assistance with confocal imaging and deconvolution analysis, U. Wolfrum (Johannes Gutenberg University of Mainz) for harmonin b–specific antibodies, H. Thompson for statistical analysis, and A. Case, B. Keats and M. Havens for discussions and comments on the manuscript.
F.R. may materially benefit financially through stock options in Isis Pharmaceuticals. M.L.H. and F.R. have patents pending with the United States Patent and Trademark Office for the ASOs and the targeting approach.
Supplementary Figures 1–10 and Supplementary Table 1 (PDF 3338 kb)
Ush1c.216AA mice treated with ASO-29. This video shows four 1-month-old mice. Two representative heterozygous (Ush1c.216GA) mice (top row) and homozygous mutant mice (Ush1c.216AA) (bottom row), one of each group treated with ASO-C (left) and one with ASO-29 (right). The ASO-C treated mutant exhibits characteristic circling behavior and hyperactivity (bottom left), whereas the ASO-29-treated mouse (bottom right) is indistinguishable from the heterozygous mice (top). (MOV 2547 kb)
Behavioral response to acoustic stimuli in Ush1c.216AA mice treated with ASO-29. This video shows four 2-month-old mice. Two representative heterozygous (Ush1c.216GA) mice (top row) and homozygous mutant mice (Ush1c.216AA) (bottom row), one of each group treated with ASO-C (left) and one with ASO-29 (right). Opaque dividers were inserted between the cages to blind the mice to each other. A whistle blow (∼3-16 kHz and 90-110 dB SPL; Supplementary Fig. 6) was activated after acclimation to the environment. This acoustic stimulus occurs 2.9 s into the video and persists for 0.9 s. A startle response, indicated by a rapid body movement, followed by freezing (a period of watchful immobility), suggests, qualitatively, that the heterozygote mice (GA) and the mutant 216AA mouse treated with ASO-29 could hear the acoustic stimulation. The 216AA mutant mouse treated with ASO-C showed no visible response to the acoustic stimulus. (MOV 2776 kb)
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Lentz, J., Jodelka, F., Hinrich, A. et al. Rescue of hearing and vestibular function by antisense oligonucleotides in a mouse model of human deafness. Nat Med 19, 345–350 (2013). https://doi.org/10.1038/nm.3106
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