Jeng, Jing-Yi;
Carlton, Adam J;
Goodyear, Richard J;
Chinowsky, Colbie;
Ceriani, Federico;
Johnson, Stuart L;
Sung, Tsung-Chang;
... Marcotti, Walter; + view all
(2022)
AAV-mediated rescue of Eps8 expression in vivo restores hair-cell function in a mouse model of recessive deafness.
Molecular Therapy - Methods and Clinical Development
, 26
pp. 355-370.
10.1016/j.omtm.2022.07.012.
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AAV-mediated rescue of Eps8 expression in vivo restores hair-cell function in a mouse model of recessive deafness.pdf - Published Version Download (6MB) | Preview |
Abstract
The transduction of acoustic information by hair cells depends upon mechanosensitive stereociliary bundles that project from their apical surface. Mutations or absence of the stereociliary protein EPS8 cause deafness in humans and mice, respectively. Eps8 knockout mice (Eps8−/−) have hair cells with immature stereocilia and fail to become sensory receptors. Here, we show that exogenous delivery of Eps8 using Anc80L65 in P1–P2 Eps8−/− mice in vivo rescued the hair bundle structure of apical-coil hair cells. Rescued hair bundles correctly localize EPS8, WHIRLIN, MYO15, and BAIAP2L2, and generate normal mechanoelectrical transducer currents. Inner hair cells with normal-looking stereocilia re-expressed adult-like basolateral ion channels (BK and KCNQ4) and have normal exocytosis. The number of hair cells undergoing full recovery was not sufficient to rescue hearing in Eps8−/− mice. Adeno-associated virus (AAV)-transduction of P3 apical-coil and P1–P2 basal-coil hair cells does not rescue hair cells, nor does Anc80L65-Eps8 delivery in adult Eps8−/− mice. We propose that AAV-induced gene-base therapy is an efficient strategy to recover the complex hair-cell defects in Eps8−/− mice. However, this therapeutic approach may need to be performed in utero since, at postnatal ages, Eps8−/− hair cells appear to have matured or accumulated damage beyond the point of repair.
| Type: | Article |
|---|---|
| Title: | AAV-mediated rescue of Eps8 expression in vivo restores hair-cell function in a mouse model of recessive deafness |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.omtm.2022.07.012 |
| Publisher version: | https://doi.org/10.1016/j.omtm.2022.07.012 |
| Language: | English |
| Additional information: | © 2022 The Author(s). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
| Keywords: | mouse, auditory, cochlea, deafness, AAVs, gene therapy, stereocilia, exocytosis, Eps8, development |
| UCL classification: | UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > The Ear Institute UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10156994 |
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