Neonatal AAV gene therapy rescues hearing in a mouse model of SYNE4 deafness

Shahar Taiber, Roie Cohen, Ofer Yizhar-Barnea, David Sprinzak, Jeffrey R. Holt*, Karen B. Avraham*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

Abstract

Genetic variants account for approximately half the cases of congenital and early-onset deafness. Methods and technologies for viral delivery of genes into the inner ear have evolved over the past decade to render gene therapy a viable and attractive approach for treatment. Variants in SYNE4, encoding the protein nesprin-4, a member of the linker of nucleoskeleton and cytoskeleton (LINC), lead to DFNB76 human deafness. Syne4−/− mice have severe-to-profound progressive hearing loss and exhibit mislocalization of hair cell nuclei and hair cell degeneration. We used AAV9-PHP.B, a recently developed synthetic adeno-associated virus, to deliver the coding sequence of Syne4 into the inner ears of neonatal Syne4−/− mice. Here we report rescue of hair cell morphology and survival, nearly complete recovery of auditory function, and restoration of auditory-associated behaviors, without observed adverse effects. Uncertainties remain regarding the durability of the treatment and the time window for intervention in humans, but our results suggest that gene therapy has the potential to prevent hearing loss in humans with SYNE4 mutations.

Original languageEnglish
Article numbere13259
JournalEMBO Molecular Medicine
Volume13
Issue number2
DOIs
StatePublished - 5 Feb 2021

Funding

FundersFunder number
Foundation Pour L?Audition
Foundation Pour L’Audition
National Institutes of Health/NIDCD
Tucker-Davis Technologies
National Institute on Deafness and Other Communication DisordersR01DC011835
United States - Israel Binational Science Foundation01027150
Capita Foundation
Horizon 2020 Framework Programme682161
European Research Council
United States-Israel Binational Science Foundation
Israel Science Foundation3499/19
Tel Aviv University
Sackler Faculty of Medicine, Tel-Aviv University

    Keywords

    • DFNB76
    • Nesprin-4
    • SYNE4
    • deafness
    • gene therapy

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