Restoration, Not Bypass: Otoferlin Gene Therapy and a New Era in Hearing Loss Treatment.

A translational framework for early-phase inner-ear gene therapy: clinical trial design, regulatory strategy, and ethical considerations.

The genetics of hearing loss is transitioning from a diagnostic modality to an interventional one, with emphasis on emerging gene-based therapies, clinical trial design, regulatory and ethical considerations, and practical implications for otolaryngologists as biologic treatment enters clinical practice.

Reprogramming translation for rare disease therapy: challenges posed by large genes

This study offers the most compelling clinical evidence so far that gene replacement therapy can safely restore signi fi cant hearing in children with OTOF-related deafness, with bene fi ts lasting up to 2.5 years, setting a new standard for treating inherited sensory disorders.

Advances towards biological hearing restoration by genetic reprogramming.

PURPOSE OF REVIEW Advances in genetic reprogramming and groundbreaking first-in-human gene therapy trials have generated significant momentum for treating sensorineural hearing loss. This review evaluates the expanding potential of biological approaches for hearing restoration. RECENT FINDINGS The mammalian organ of Corti possesses limited natural regenerative capacity. Recent studies are attempting to restore hearing by genetically reprogramming supporting cells into hair cells. While merely modulating cell signaling pathways in the inner ear is currently insufficient to regenerate hair cells, expressing hair cell-specific specific transcription factors can partially activate hair cell identity. However, current attempts at reprogramming are only partially successful, yielding only immature and nonfunctional "hair cell-like cells." SUMMARY To develop viable gene therapies, future research must identify the molecular mechanisms that maintain supporting cell identity in the mature cochlea. Targeting and suppressing these gene networks in addition to activating hair cell gene networks is essential to improve the complete transition of supporting cells into functional hair cells, paving the way for translating these regenerative strategies into effective clinical treatments.

Resolving early cochlear inflammation prevents lasting damage from noise exposure

Imaging-identified round window niche veil and intratympanic therapy efficacy in sudden sensorineural hearing loss

Abstract Background Intratympanic (IT) therapy is a common procedure to deliver drugs into the cochlear for the treatment of inner ear diseases. Round window niche veil (RWNV) is an extra anatomical barrier potentially impending drug delivery. However, RWNV’s identification is neglected, and its effect on IT efficacy awaits investigation. Methods Patients with unilateral sudden sensorineural hearing loss (SSNHL), undergoing temporal bone HRCT examination and initiating IT therapy were enrolled and followed up for 30 days. Participants were independently assessed and identified into RWNV+ and RWNV− by an imaging-based workflow. Primary outcome was response (clinically important hearing improvement ≥10 dB) to IT therapy, whilst secondary outcomes included pure-tone average threshold (PTA) and word recognition score (WRS) gains from baseline. Frequency-specific hearing threshold, WRS at varying levels, and haring levels by severity were also reported. Logistic or linear regression models were employed to investigate the IT therapy outcomes in RWNV+ versus RWNV−. Results A total of 169 patients (44.4 ± 12.6 yr; 52.1% females) were included and stratified into RWNV+ (56.2%) and RWNV− (43.8%), with good inter-reader agreement (Kappa, 0.798–0.892). Clinical response to IT administration was achieved in 34.7% of RWNV+ versus 50.0% of RWNV− cases. RWNV+ associated with inferior response probability (OR = 0.441; 95% CI, 0.216–0.902), independent of clinical prevalent variables. RWNV+ potentially synergized with established risk factors (prolonged course, vertigo) and further diminished efficacy. RWNV+ also correlated with poorer PTA0.5–4 kHz gains (β = −5.16; 95% CI, −9.86 to −0.47) and worser WRS at 70–90 dB SPL (p < 0.05). Conclusions RWNV identified by a HRCT-based workflow is independently associates with inferior IT therapy efficacy in SSNHL. Pre-treatment imaging assessment may help to predict potential benefits from IT therapy.

Cochlear Implantation in Sickle Cell Disease: A Systematic Review of Feasibility and Outcomes.

INTRODUCTION Sickle cell disease (SCD) is associated with systemic complications, including sensorineural hearing loss (SNHL) from microvascular occlusion and chronic inflammation. Although reports link SCD to higher rates of SNHL, current evidence is limited by small sample size, varied audiologic methods, and lack of standardized screening. This systematic review summarizes available literature on SNHL and cochlear implantation (CI) in SCD. METHODS A literature search of PubMed MEDLINE, Embase, Scopus, Web of Science, and CINAHL identified 79 citations. After removal of duplicates, 35 records were screened in Rayyan. Studies published between January 1, 2000, and June 30, 2025, were eligible if they reported patients with SCD who developed hearing loss and underwent CI. Nine full texts were reviewed, and 4 met the inclusion criteria. Screening and review were performed independently by 2 authors per PRISMA guidelines. RESULTS Across 4 case reports, a total of 5 patients with SCD underwent CI, ranging in age from 2 to 42 years. Four presented with bilateral severe-to-profound SNHL and one with unilateral loss. Implantation was technically feasible in all cases, including patients with cochlear fibrosis or ossification requiring modified insertion techniques. Postoperative outcomes were favorable: all patients demonstrated reliable device function and low impedances. Only 60% showed meaningful auditory benefit, characterized by improved functional speech perception in 2 patients (40%) and access to the speech frequency range with hearing testing going from moderate/profound hearing loss to mild hearing loss in 3 patients (60%). Complications occurred in 2 patients (40%): one developed unilateral middle ear infection leading to meningitis, and another experienced a postoperative pulmonary embolism requiring anticoagulation. The remaining 3 patients (60%) had uncomplicated recoveries with reported improved hearing from moderate/profound hearing loss to mild hearing loss post implantation. CONCLUSION While CI appears feasible in SCD, our findings suggest that additional data are needed to assess its effectiveness in this patient population. However, evidence is limited to case reports, and complications such as thromboembolism and rapid cochlear fibrosis highlight the need for close perioperative management. More comprehensive studies with larger sample size are required to define surgical risk, optimize management, and establish best practices for timely implantation in this population.