Hair Cell Regeneration and Gene Therapy in Sensory Systems

Loss of sensory hair cells in the inner ear or vestibular organs leads to permanent deficits in hearing and balance. Unlike non-mammalian vertebrates, adult mammals exhibit very limited capacity for hair cell renewal, leaving gene therapy and stem cell activation as promising avenues for functional recovery. Recent advances in single-cell transcriptomics have mapped the diversity of cell types and uncovered progenitor populations capable of regeneration. Concurrently, improved viral vectors, notably designer adeno-associated viruses (AAVs), have enhanced gene delivery to hair cells and supporting cells, enabling the introduction of therapeutic transgenes such as those encoding otoferlin or channel-like proteins. Preclinical studies in rodents have demonstrated partial rescue of auditory thresholds and synaptic transmission, while early clinical trials in children with hereditary forms of deafness have shown restoration of hearing function without serious adverse events. Interdisciplinary progress in molecular profiling, vector design and clinical translation is converging on scalable strategies to repair or replace hair cells, offering new hope for sensorineural hearing loss and balance disorders worldwide.

Research from Nature Portfolio

In a first-in-human trial, bilateral administration of a dual-serotype AAV carrying the human OTOF gene in children with DFNB9 resolved profound deafness, restoring auditory brainstem response thresholds to functional levels and recovering speech perception and sound-source localisation without serious adverse events. This milestone underscores the safety and efficacy of bilateral AAV gene therapy for monogenic hearing loss.

A high-resolution single-cell transcriptomic atlas of human utricular sensory epithelia has revealed unexpected regenerative activity in vestibular organs from disease-affected donors. Markers for hair cell precursors were found at significantly higher frequencies, and trajectory analyses identified distinct gene expression programmes involving Wnt and IGF-1 pathways that drive supporting cells towards hair cell fates. This dataset provides a foundational resource for therapeutic target discovery.

Hair Cell Regeneration and Gene Therapy in Sensory Systems publication trend

The graph below shows the total number of articles in hair cell regeneration and gene therapy in sensory systems across all publications each year (not limited to Nature Index journals).

Technical terms

Hair cell: specialised mechanosensory receptor in the inner ear or vestibular organs that converts mechanical stimuli into electrical signals.

Supporting cell: non-sensory epithelial cell that maintains structure, secretes signalling factors and can act as a progenitor for hair cell regeneration.

Adeno-associated virus (AAV): a non-pathogenic viral vector commonly used to deliver therapeutic genes to target cells in vivo.

Transdifferentiation: direct conversion of one mature cell type into another without reverting to a pluripotent state.

Lgr5: a G-protein coupled receptor that marks Wnt-responsive stem or progenitor cells in various tissues.

Otoferlin: a calcium-sensing protein essential for synaptic vesicle exocytosis in auditory inner hair cells; its mutation causes DFNB9 deafness.

Transgene: an engineered gene introduced into an organism’s genome to confer new functions or correct genetic defects.

References

1. Bilateral gene therapy in children with autosomal recessive deafness 9: single-arm trial results. Nature Medicine (2024).
2. Single-cell transcriptomic atlas reveals increased regeneration in diseased human inner ear balance organs. Nature Communications (2024).
3. Lgr5-Positive Supporting Cells Generate New Hair Cells in the Postnatal Cochlea. Stem Cell Reports (2014).
4. A dual‐AAV approach restores fast exocytosis and partially rescues auditory function in deaf otoferlin knock‐out mice. EMBO Molecular Medicine (2018).
5. scRNA-Seq reveals distinct stem cell populations that drive hair cell regeneration after loss of Fgf and Notch signaling. eLife (2019).