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Background <p>Sensorineural hearing loss (SNHL) represents the most common sensory deficit in humans and is increasingly prevalent with aging. Despite diverse etiologies, irreversible degeneration of cochlear hair cells and neurons remains a final pathway for auditory decline.</p> Objective <p>This narrative review synthesizes current preclinical and early clinical evidence on gene- and stem cell–based strategies for congenital and acquired SNHL, highlighting translational progress, delivery innovations, and persisting limitations.</p> Methods <p>A structured literature and registry search (PubMed, Embase, Scopus, Web of Science, ClinicalTrials.gov, EudraCT) was conducted using Boolean combinations of disease-, gene-, vector-, and delivery-related terms. From 140 initial records, 46 eligible studies were included after full-text screening. Data were qualitatively analyzed across two streams—human clinical (gene therapy) and preclinical/experimental (gene editing, RNA-based modulation, stem-cell regeneration).</p> Results <p>Two independent first-in-human AAV-mediated OTOF replacement trials in children with DFNB9 demonstrated partial restoration of hearing, establishing the first clinical proof-of-concept for cochlear gene therapy. Preclinical studies confirm durable auditory and vestibular rescue using dual-AAV systems, while CRISPR-based editing, antisense oligonucleotides (ASOs), and RNA interference (RNAi) approaches show mechanistic feasibility. Induced pluripotent stem cells (iPSCs) and inner-ear organoids replicate key developmental pathways, supporting modeling and future cellular repair. Delivery precision via the round window, oval window, and microneedle systems remains the major translational bottleneck.</p> Conclusions <p>Gene- and cell-based approaches are transforming auditory regenerative medicine. Among them, AAV-mediated OTOF replacement has reached clinical validation, whereas CRISPR, ASO/RNAi, and iPSC-derived regeneration continue at advanced preclinical stages. Future success will depend on refining delivery, ensuring long-term safety, and harmonizing ethical and regulatory oversight.</p>

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Stem cell–based and gene editing strategies in the treatment of congenital and acquired sensorineural hearing loss: a narrative review

  • 期刊论文

  • 发表日期：

    2026年1月6日

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  • Alireza Moradi,
  • Seied-Reza Seied-Mohammad Doulabi,
  • Ashkan Sherafat Vaziri,
  • Silke Helbig,
  • Mehran Baghi

摘要

Background

Sensorineural hearing loss (SNHL) represents the most common sensory deficit in humans and is increasingly prevalent with aging. Despite diverse etiologies, irreversible degeneration of cochlear hair cells and neurons remains a final pathway for auditory decline.

Objective

This narrative review synthesizes current preclinical and early clinical evidence on gene- and stem cell–based strategies for congenital and acquired SNHL, highlighting translational progress, delivery innovations, and persisting limitations.

Methods

A structured literature and registry search (PubMed, Embase, Scopus, Web of Science, ClinicalTrials.gov, EudraCT) was conducted using Boolean combinations of disease-, gene-, vector-, and delivery-related terms. From 140 initial records, 46 eligible studies were included after full-text screening. Data were qualitatively analyzed across two streams—human clinical (gene therapy) and preclinical/experimental (gene editing, RNA-based modulation, stem-cell regeneration).

Results

Two independent first-in-human AAV-mediated OTOF replacement trials in children with DFNB9 demonstrated partial restoration of hearing, establishing the first clinical proof-of-concept for cochlear gene therapy. Preclinical studies confirm durable auditory and vestibular rescue using dual-AAV systems, while CRISPR-based editing, antisense oligonucleotides (ASOs), and RNA interference (RNAi) approaches show mechanistic feasibility. Induced pluripotent stem cells (iPSCs) and inner-ear organoids replicate key developmental pathways, supporting modeling and future cellular repair. Delivery precision via the round window, oval window, and microneedle systems remains the major translational bottleneck.

Conclusions

Gene- and cell-based approaches are transforming auditory regenerative medicine. Among them, AAV-mediated OTOF replacement has reached clinical validation, whereas CRISPR, ASO/RNAi, and iPSC-derived regeneration continue at advanced preclinical stages. Future success will depend on refining delivery, ensuring long-term safety, and harmonizing ethical and regulatory oversight.