ArticleMolecular therapy : the journal of the American Society of Gene Therapy2025
Antisense oligonucleotide therapy mitigates autosomal dominant progressive hearing loss in a murine model of human DFNA2.
Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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Who cites it
4 citing papers in PubMed.
- Genetic Findings in Seven Cochlear Implanted Patients with Severe-to-Profound Hearing Loss.Genes · 2026Article
- Long-term restoration of auditory function in a DFNA2 mouse model by adenine base editing.EMBO molecular medicine · 2026Article
- Connexin 26 in Hearing Health and Disease: StructuralFoundations, Mutation Mechanisms, and Therapeutic Perspectives.International journal of molecular sciences · 2026Review
- Recent preclinical and clinical advances in gene therapy for hereditary hearing loss.Molecules and cells · 2025Review
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11 authors.
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Abstract
Hearing loss is the most common sensory disorder, with a substantial proportion caused by genetic mutations. KCNQ4, a voltage-gated potassium channel highly expressed in cochlear outer hair cells, is a common genetic etiology implicated in autosomal dominant progressive hearing loss (DFNA2). The dominant-negative KCNQ4 p.W276S (c.827G>C) mutation represents a mutational hotspot in DFNA2, yet no effective treatments exist. Here, we developed allele-preferential antisense oligonucleotides (ASOs) targeting this dominant-negative KCNQ4 mutation. In a systemic in vitro screen, ASO-123 demonstrated a knockdown of mutant Kcnq4 while preserving wild-type transcripts. In a Kcnq4 p.W277S knockin mouse model mimicking DFNA2, ASO-123 preferentially suppressed mutant transcripts, attenuated progressive hearing loss, and improved outer hair cell survival while enhancing their electrophysiologic function. Comprehensive transcriptomic analyses further validated the efficacy of ASO-123. Thus, our findings establish ASO-based therapy as a promising strategy for treating hereditary hearing loss caused by dominant-negative KCNQ4 mutations.
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