The rise of cochlear gene therapy

Lukas D Landegger; Ellen Reisinger; François Lallemend; Steffen R Hage; Dirk Grimm; Christopher R Cederroth

doi:10.1016/j.ymthe.2024.11.012

The rise of cochlear gene therapy

Mol Ther. 2024 Nov 8:S1525-0016(24)00739-1. doi: 10.1016/j.ymthe.2024.11.012. Online ahead of print.

Authors

Lukas D Landegger¹, Ellen Reisinger², François Lallemend³, Steffen R Hage⁴, Dirk Grimm⁵, Christopher R Cederroth⁶

Affiliations

¹ Department of Otolaryngology, Vienna General Hospital, Medical University of Vienna, Vienna, Austria; Department of Otolaryngology - Head and Neck Surgery, Stanford University School of Medicine, Palo Alto, CA, USA.
² Gene Therapy for Hearing Impairment and Deafness, Tübingen Hearing Research Center, Department of Otolaryngology - Head and Neck Surgery, University of Tübingen, Tübingen, Germany.
³ Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
⁴ Neurobiology of Social Communication, Tübingen Hearing Research Center, Department of Otolaryngology - Head and Neck Surgery, University of Tübingen, Medical Center, Tübingen, Germany; Werner Reichardt Centre for Integrative Neuroscience, University of Tübingen, Tübingen, Germany.
⁵ Department of Infectious Diseases/Virology, Section Viral Vector Technologies, Medical Faculty and Faculty of Engineering Sciences, BioQuant Center BQ0030, University of Heidelberg, Heidelberg, Germany; German Center for Infection Research (DZIF) and German Center for Cardiovascular Research (DZHK), partner site Heidelberg, Heidelberg, Germany.
⁶ Translational Hearing Research, Tübingen Hearing Research Center, Department of Otolaryngology - Head and Neck Surgery, University of Tübingen, Tübingen, Germany; Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden. Electronic address: christopher.cederroth@uni-tuebingen.de.

PMID: 39520052
DOI: 10.1016/j.ymthe.2024.11.012

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.

Publication types

Review