Figure 1.

AAV8-Whirlin Gene Therapy Restores Whirlin Expression in Infected Utricular Hair Cells

(A) Schematic of the study. The inner ear is important for balance function. Vestibular hair cells detect rotational inputs as well as linear and gravitational acceleration by the deflection of their stereocilia bundles. This information is transmitted by the superior and inferior vestibular nerves to the central vestibular system for processing. In this study, we examined whether AAV8-whirlin gene therapy delivered through the posterior semicircular canal can restore vestibular hair cell stereocilia morphology and balance function in whirler mice. The predominant long isoform of whirlin used in this study encodes a scaffolding protein with three PDZ domains and one proline-rich domain. The region recognized by the anti-whirlin antibody is indicated by the purple line. ab, antibody. (B) Utricular hair cells in a phenotypically normal control mouse (whrn^+/wi, P30) show immunolocalization of whirlin (green) at the tips of the stereocilia (red). Examples of whirlin expression are shown with white arrows. (C) Utricular hair cells in a whirler untreated control mouse (whrn^wi/wi, no gene therapy, P30) lack whirlin expression at the stereocilia tips. In addition, whirler utricular hair cells have aberrantly short stereocilia bundles. (D) AAV8-whirlin gene therapy delivered via the posterior semicircular canal at P4 restored whirlin expression at the stereocilia tips and initiated elongation of stereocilia in infected utricular hair cells in a P30 whirler mouse. Examples of whirlin expression are indicated with white arrows. (E) Distribution of utricular hair cell infection efficiency in all whirler ears that received AAV8-whirlin gene therapy.