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Review
. 2025 Jun 4;33(6):2343-2349.
doi: 10.1016/j.ymthe.2024.11.012. Epub 2024 Nov 8.

The rise of cochlear gene therapy

Lukas D Landegger  1 , Ellen Reisinger  2 , François Lallemend  3 , Steffen R Hage  4 , Dirk Grimm  5 , Christopher R Cederroth  6
Affiliations
Review

The rise of cochlear gene therapy

Lukas D Landegger et al. Mol Ther. .

Abstract

Recent evidence provides strong support for the safe and effective use of gene therapy in humans with hearing loss. By means of a single local injection of a set of adeno-associated virus (AAV) vectors, hearing was partially restored in several children with neurosensory nonsyndromic autosomal recessive deafness 9 (DFNB9), harboring variants in the OTOF gene. Current research focuses on refining endoscopic and transmastoid injection procedures to reduce risks of side effects, as emerging evidence suggests bidirectional fluid exchanges between the ear and the brain. Moreover, gene editing approaches and novel AAV capsids are successfully tested in animal models and will likely lead to enhanced targeting of the cochlea. Here, we cover the recent advances in cochlear gene therapy, provide an overview of the translational potential of these new approaches for existing and future clinical trials, and highlight the translational implications that remain to be determined for their application in humans.

Keywords: CSF; NHP; auditory; cochlea; gene therapy; hearing loss; off-targeting; otoferlin.

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Conflict of interest statement

Declaration of interests L.D.L. has received research funding from Decibel Therapeutics/Regeneron Pharmaceuticals and Amgen and has worked as an independent consultant for Conclave Capital and Gerson Lehrman Group. E.R. is co-inventor on a patent application for dual-AAV vectors to restore hearing. The University Medical Center Göttingen has licensed the rights to these parts of the patent exclusively to Akouos, Inc., USA. C.R.C. has a pending patent application for the delivery of therapeutics to the inner ear via the cisterna magna (international patent application no. PCT/US22/82225, title: “CSF transport pathway for delivery of agents to the inner ear”).

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