Direct Delivery of Antisense Oligonucleotides to the Middle and Inner Ear Improves Hearing and Balance in Usher Mice

Mol Ther. 2020 Dec 2;28(12):2662-2676. doi: 10.1016/j.ymthe.2020.08.002. Epub 2020 Aug 5.


Usher syndrome is a syndromic form of hereditary hearing impairment that includes sensorineural hearing loss and delayed-onset retinitis pigmentosa (RP). Type 1 Usher syndrome (USH1) is characterized by congenital profound sensorineural hearing impairment and vestibular areflexia, with adolescent-onset RP. Systemic treatment with antisense oligonucleotides (ASOs) targeting the human USH1C c.216G>A splicing mutation in a knockin mouse model of USH1 restores hearing and balance. Herein, we explore the effect of delivering ASOs locally to the ear to treat hearing and vestibular dysfunction associated with Usher syndrome. Three localized delivery strategies were investigated in USH1C mice: inner ear injection, trans-tympanic membrane injection, and topical tympanic membrane application. We demonstrate, for the first time, that ASOs delivered directly to the ear correct Ush1c expression in inner ear tissue, improve cochlear hair cell transduction currents, restore vestibular afferent irregularity, spontaneous firing rate, and sensitivity to head rotation, and successfully recover hearing thresholds and balance behaviors in USH1C mice. We conclude that local delivery of ASOs to the middle and inner ear reach hair cells and can rescue both hearing and balance. These results also demonstrate the therapeutic potential of ASOs to treat hearing and balance deficits associated with Usher syndrome and other ear diseases.

Keywords: USH1C; Usher syndrome; antisense oligonucleotides; balance; deafness; hearing; inner ear; retinitis pigmentosa.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Topical
  • Animals
  • Animals, Newborn
  • Cell Cycle Proteins / genetics*
  • Cytoskeletal Proteins / genetics*
  • Disease Models, Animal
  • Ear, Middle / drug effects*
  • Female
  • Gene Knock-In Techniques
  • Genetic Therapy / methods*
  • Hair Cells, Auditory / drug effects*
  • Hair Cells, Auditory / metabolism
  • Hearing / drug effects
  • Injections
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mutation*
  • Oligonucleotides, Antisense / administration & dosage*
  • Tympanic Membrane / drug effects
  • Usher Syndromes / genetics*
  • Usher Syndromes / therapy*
  • Vestibule, Labyrinth / drug effects*
  • Vestibule, Labyrinth / metabolism


  • Cell Cycle Proteins
  • Cytoskeletal Proteins
  • Oligonucleotides, Antisense
  • USH1C protein, human

Supplementary concepts

  • Usher Syndrome, Type IC