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Cited by 230Hearing, Cochlea, Tinnitus, GeneticsVirus-based gene therapy researchRNA Interference and Gene Delivery

A dual‐AAV approach restores fast exocytosis and partially rescues auditory function in deaf otoferlin knock‐out mice

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Al‐Moyed, Hanan, Cepeda, Andreia P, Jung, SangYong, Moser, Tobias, Kügler, Sebastian, Reisinger, Ellen·2019·EMBO Molecular Medicine
DOI 10.15252/emmm.201809396PMC PMC6328916
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Abstract

Normal hearing and synaptic transmission at afferent auditory inner hair cell (IHC) synapses require otoferlin. Deafness DFNB9, caused by mutations in the OTOF gene encoding otoferlin, might be treated by transferring wild‐type otoferlin cDNA into IHCs, which is difficult due to the large size of this transgene. In this study, we generated two adeno‐associated viruses (AAVs), each containing half of the otoferlin cDNA. Co‐injecting these dual‐AAV2/6 half‐vectors into the cochleae of 6‐ to 7‐day‐old otoferlin knock‐out ( Otof −/− ) mice led to the expression of full‐length otoferlin in up to 50% of IHCs. In the cochlea, otoferlin was selectively expressed in auditory hair cells. Dual‐AAV transduction of Otof −/− IHCs fully restored fast exocytosis, while otoferlin‐dependent vesicle replenishment reached 35–50% of wild‐type levels. The loss of 40% of synaptic ribbons in these IHCs could not be prevented, indicating a role of otoferlin in early synapse maturation. Acoustic clicks evoked auditory brainstem responses with thresholds of 40–60 dB. Therefore, we propose that gene delivery mediated by dual‐AAV vectors might be suitable to treat deafness forms caused by mutations in large genes such as OTOF .

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  • Another study performed cochlear injections of dual AAV6 trans-splicing or hybrid vectors in Otof -/-mice, achieving 31-37% otoferlin protein levels in the inner hair cells compared to wild-type, which was sufficient to partially restore auditory function in deaf mice.

    “Another study performed cochlear injections of dual AAV6 trans-splicing or hybrid vectors in Otof -/-mice, achieving 31-37% otoferlin protein levels in the inner hair cells compared to wild-type, which was sufficient to partially restore auditory function in deaf mice [109].”

    From Circumventing the packaging limit of AAV-mediated gene replacement therapy for neurological disorders (2022) · cites this paper as [109]

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Cited by

Sorted by citations

Authors
Al‐Moyed, H., Cepeda, A. P., Jung, S., Moser, T., Kügler, S., & Reisinger, E.
Affiliations
Universitätsmedizin Göttingen (DE)
Corresponding author
  • Kügler, Sebastian
  • Reisinger, Ellen
ORCID
Venue
EMBO Molecular Medicine
Publisher
Springer Science and Business Media LLC
Published
2018-12-03
Volume
11
Issue
1
ISSN
  • 1757-4676 (ISSN-L)
  • 1757-4684
DOI
10.15252/emmm.201809396
PMC
PMC6328916
OpenAlex
W2902016625
Cited by
230
References
5
Citations by year
2026: 27 · 2025: 41 · 2024: 45 · 2023: 34 · 2022: 17 · 2021: 22 · 2020: 31 · 2019: 10 · 2018: 2
FWCI
10.47
Type
journal article
Language
en
Open access
Licence
Locations
  • EMBO Molecular Medicine (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • GoeScholar The Publication Server of the Georg-August-Universität Göttingen (Georg-August-Universität Göttingen) (submittedVersion, cc-by)
  • MPG.PuRe (Max Planck Society) (submittedVersion, other-oa)
Funders
  • University Medical Center Goettingen
  • Goettingen Graduate School for Neuroscience, Biophysics and Molecular Biosciences
  • Deutsche Forschungsgemeinschaft (SFB889, CNMPB)
  • Center for Nanoscale Microscopy and Physiology of the Brain
Topics
  • Life Sciences › Neuroscience › Sensory Systems › Hearing, Cochlea, Tinnitus, Genetics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
Keywords
otoferlin, adeno-associated virus vectors, inner hair cells, synaptic ribbons, synapse maturation, gene therapy, hearing loss, auditory brainstem response, vesicle replenishment
MeSH terms
Dependovirus, Animals, Deafness, Exocytosis, Genetic Vectors, Hair Cells, Auditory, Inner, Membrane Proteins, Transduction, Genetic, Genetic Therapy, Treatment Outcome, Mice, Knockout

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