Local gene therapy durably restores vestibular function in a mouse model of Usher syndrome type 1G

Proc Natl Acad Sci U S A. 2017 Sep 5;114(36):9695-9700. doi: 10.1073/pnas.1708894114. Epub 2017 Aug 23.

Abstract

Our understanding of the mechanisms underlying inherited forms of inner ear deficits has considerably improved during the past 20 y, but we are still far from curative treatments. We investigated gene replacement as a strategy for restoring inner ear functions in a mouse model of Usher syndrome type 1G, characterized by congenital profound deafness and balance disorders. These mice lack the scaffold protein sans, which is involved both in the morphogenesis of the stereociliary bundle, the sensory antenna of inner ear hair cells, and in the mechanoelectrical transduction process. We show that a single delivery of the sans cDNA by the adenoassociated virus 8 to the inner ear of newborn mutant mice reestablishes the expression and targeting of the protein to the tips of stereocilia. The therapeutic gene restores the architecture and mechanosensitivity of stereociliary bundles, improves hearing thresholds, and durably rescues these mice from the balance defects. Our results open up new perspectives for efficient gene therapy of cochlear and vestibular disorders by showing that even severe dysmorphogenesis of stereociliary bundles can be corrected.

Keywords: Usher; balance; gene; mouse; therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • DNA, Complementary / administration & dosage
  • DNA, Complementary / genetics
  • Dependovirus / genetics
  • Disease Models, Animal
  • Evoked Potentials, Auditory, Brain Stem
  • Genetic Therapy / methods
  • Genetic Vectors
  • Hair Cells, Auditory / pathology
  • Hair Cells, Auditory / physiology
  • Humans
  • Mice
  • Mice, Knockout
  • Microscopy, Electron, Scanning
  • Nerve Tissue Proteins / deficiency
  • Nerve Tissue Proteins / genetics
  • Usher Syndromes / genetics*
  • Usher Syndromes / physiopathology
  • Usher Syndromes / therapy*
  • Vestibule, Labyrinth / pathology
  • Vestibule, Labyrinth / physiopathology

Substances

  • DNA, Complementary
  • Nerve Tissue Proteins
  • Sans protein, mouse

Supplementary concepts

  • Usher Syndrome, Type IG