The Key to Hearing: Advancements in the Diagnosis and Therapy of Hearing Loss Genes
Cochlear implantation and gene therapy: can they be compatible?
Cochlear implantation is currently the treatment of choice for children with severe to profound sensorineural hearing impairment (SNHI). Although most patients with SNHI have good speech perception after cochlear implantation, they do not regain "natural hearing" and cannot enjoy music satisfactorily. Cochlear implants convert external sounds into electrical signals and function only as a mechanical prosthesis. Cochlear implants cannot provide full recovery of hearing sensitivity and/or restoration of the native inner ear sensory epithelium. Furthermore, the benefits of cochlear implants may be limited due to the involvement of retrocochlear pathologies. Therefore, new biological therapeutic approaches based on gene transfer and gene editing tools are being developed to address these unmet clinical needs. It can be envisioned that gene therapy for SNHI will start from certain scenarios: (1) OTOF-related SNHI, as recent animal studies have demonstrated the potential of gene therapy to reverse cochlear pathologies caused by OTOF mutations; (2) syndromic hearing loss, such as Usher syndrome, as there are already FDA-approved gene therapies for ocular or neurological diseases; (3) SLC26A4-related SNHI, as there may be a therapeutic window for gene therapy due to the progressive/fluctuating nature of SNHI; and (4) genetic etiologies associated with poor CI outcomes, such as retrocochlear pathologies caused by PJVK mutations. In this talk, I will discuss these scenarios and present our recent data in humans and experimental models.
Gene Therapy for Hereditary Hearing Loss: From Molecular Insights to First-in-Human Trials
Hereditary hearing loss—the most common congenital sensory disorder, affecting 1–2 per 1,000 newborns—presents a unique opportunity for precision therapeutics. The cochlea is surgically accessible, fluid-sealed, and over half of cases arise from single-gene mutations. Recent breakthroughs in inner-ear biology, combined with advances in gene delivery and editing, are rapidly reshaping the therapeutic landscape. Engineered adeno-associated virus (AAV) capsids, such as Anc80L65 and next-generation AAV9 variants, now enable >80% inner-hair-cell transduction in rodents and non-human primates, while hybrid nanoparticle systems accommodate oversized or dual-vector payloads. Beyond classical gene replacement, CRISPR-based gene editing, together with precision base and prime editors, is expanding the therapeutic repertoire for mutation-specific correction. These innovations are moving toward clinical application. Phase I/II trials targeting OTOF-related auditory synaptopathy are underway, with preliminary reports showing encouraging safety and no dose-limiting ototoxicity. Our group has contributed key preclinical milestones, including proof-of-concept studies for some of the most prevalent forms of genetic deafness. Looking ahead, universal newborn genomic screening, rational vector design, and scalable GMP manufacturing will be critical for clinical translation. By integrating molecular genetics, vectorology, and clinical otology, gene therapy is poised to redefine the
Shin-ichi Usami
Country : Japan
Official Title : professor
Department :
Institute : Shinshu University
Jinsei Jung
Country : Korea
Official Title : professor
Department :
Institute : Yonsei University Hos-pital
Speaker CVA new era in precision medicine for genetic hearing loss
Hearing loss is a major global health concern, with genetic factors accounting for a significant portion of both congenital and adult-onset sensorineural hearing loss (SNHL). Recent advances in genomic technologies have enabled the identification of over 130 deafness-related genes, paving the way for precision medicine approaches. This presentation highlights translational strategies targeting specific genetic causes of hearing loss. A series of strategies exemplify how integrating genetic diagnostics, disease modeling, and targeted therapeutics can reshape the treatment paradigm for hereditary hearing loss. Precision medicine offers new hope for curative interventions, shifting the focus from amplification devices to molecularly guided therapies tailored to the underlying genetic etiology.
Revisit the Inner Ear from the Molecular viewpoint
內耳身兼聽覺與周邊平衡覺的角色,在生物感知聲波與環境訊息交換途徑佔重要地位,由已知 生理學與組織型態學的知識顯示為極其複雜器官。無論生理活動或構造建置都離不開鎖在 DNA 中的遺傳指令密碼。這半世紀以來從分子生物學技術的進展,呼應遺傳學知識的累加,以等比 級數速度提供我們擴展另一角度探索這感官構造,特別為了治療的目標,更完整了解正常與異 常內耳基因成員名單,以及其間動態相互作用的機轉,越有證據提供再生療效精進品質。
Clinical Phenotypes of Common Hearing Loss Genes in Taiwan
In Taiwan, genetic factors cause over two-thirds of newborn hearing loss cases. Understanding the common genes is crucial for timely management.The GJB2 gene is most prevalent, inherited recessively. Its c.109 G>A variant can cause mild-to-moderate loss, sometimes missed by screenings. The c.235delC variant often leads to moderate-to-profound loss, requiring early intervention like hearing aids or cochlear implants.The SLC26A4 gene (also recessive) can cause Pendred syndrome (with thyroid issues) or hearing loss with Enlarged Vestibular Aqueduct (EVA), making hearing unstable.OTOF gene variations lead to Auditory Neuropathy Spectrum Disorder (ANSD), where speech discrimination is poor despite varying hearing thresholds.MYO15A gene typically causes severe, non-progressive sensorineural hearing loss from birth.The maternally inherited MTRNR1 gene is critical; its m.1555A>G variant can cause rapid hearing deterioration with aminoglycoside antibiotics, which must be avoided. KCNQ4 c.546C>G variant is associated with early-onset high-frequency hearing loss, tinnitus, and cardiovascular comorbidities in Taiwanese adults. Early genetic testing is vital for accurate diagnosis and personalized treatment plans.
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