Engineering olivocochlear inhibition to reduce acoustic trauma

• Published in: Molecular therapy. Methods & clinical development Vol. 29; pp. 17 - 31
• Main Authors: Zhang, Yuanyuan, Hiel, Hakim, Vincent, Philippe F.Y., Wood, Megan B., Elgoyhen, Ana B., Chien, Wade, Lauer, Amanda, Fuchs, Paul A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 08-06-2023; American Society of Gene & Cell Therapy; Elsevier
• Subjects: AAV; acoustic trauma; cochlea; efferent inhibition; gain-of-function nAChRs; gene therapy; Original; cochlea; gene therapy; acoustic trauma; efferent inhibition; gain-of-function nAChRs; AAV
• ISSN: 2329-0501; 2329-0501
• DOI: 10.1016/j.omtm.2023.02.011

Efferent brain-stem neurons release acetylcholine to desensitize cochlear hair cells and can protect the inner ear from acoustic trauma. That protection is absent from knockout mice lacking efferent inhibition and is stronger in mice with a gain-of-function point mutation of the hair cell-specific nicotinic acetylcholine receptor. The present work uses viral transduction of gain-of-function receptors to restore acoustic prophylaxis to the knockout mice. Widespread postsynaptic expression of the transgene was visualized in excised tissue with a fluorophore-conjugated peptide toxin that binds selectively to hair cell acetylcholine receptors. Viral transduction into efferent knockout mice reduced the temporary hearing loss measured 1 day post acoustic trauma. The acoustic evoked-response waveform (auditory brain-stem response) recovered more rapidly in treated mice than in control mice. Thus, both cochlear amplification by outer hair cells (threshold shift) and afferent signaling (evoked-response amplitude) in knockout mice were protected by viral transduction of hair cell acetylcholine receptors. Gene therapy to strengthen efferent cochlear feedback could be complementary to existing and future therapies to prevent hearing loss, including ear coverings, hearing aids, single-gene repair, or small-molecule therapies.
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Cholinergic efferent neurons inhibit cochlear hair cells to regulate sensitivity. Consequently, mutant mice lacking the hair cell acetylcholine receptor are more sensitive to acoustic trauma. The authors use viral gene therapy to express the missing receptor, restoring a degree of acoustic protection.