Browsing by Author "Chen, Yuan-Siao"

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    Selection of viral capsids and promoters affects the efficacy of rescue of Tmprss3-deficient cochlea
    (Elsevier, 2023-08-11) Aaron, Ksenia A.; Pekrun, Katja; Atkinson, Patrick J.; Billings, Sara E.; Abitbol, Julia M.; Lee, Ina A.; Eltawil, Yasmin; Chen, Yuan-Siao; Dong, Wuxing; Nelson, Rick F.; Kay, Mark A.; Cheng, Alan G.; Otolaryngology -- Head and Neck Surgery, School of Medicine
    Adeno-associated virus (AAV)-mediated gene transfer has shown promise in rescuing mouse models of genetic hearing loss, but how viral capsid and promoter selection affects efficacy is poorly characterized. Here, we tested combinations of AAVs and promoters to deliver Tmprss3, mutations in which are associated with hearing loss in humans. Tmprss3tm1/tm1 mice display severe cochlear hair cell degeneration, loss of auditory brainstem responses, and delayed loss of spiral ganglion neurons. Under the ubiquitous CAG promoter and AAV-KP1 capsid, Tmprss3 overexpression caused striking cytotoxicity in vitro and in vivo and failed to rescue degeneration or dysfunction of the Tmprss3tm1/tm1 cochlea. Reducing the dosage or using AAV-DJ-CAG-Tmprss3 diminished cytotoxicity without rescue of the Tmprss3tm1/tm1 cochlea. Finally, the combination of AAV-KP1 capsid and the EF1α promoter prevented cytotoxicity and reduced hair cell degeneration, loss of spiral ganglion neurons, and improved hearing thresholds in Tmprss3tm1/tm1 mice. Together, our study illustrates toxicity of exogenous genes and factors governing rescue efficiency, and suggests that cochlear gene therapy likely requires precisely targeted transgene expression.
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    TMPRSS3 expression is limited in spiral ganglion neurons: implication for successful cochlear implantation
    (BMJ, 2022) Chen, Yuan-Siao; Cabrera, Ernesto; Tucker, Brady J.; Shin, Timothy J.; Moawad, Jasmine V.; Totten, Douglas J.; Booth, Kevin T.; Nelson, Rick F.; Otolaryngology -- Head and Neck Surgery, School of Medicine
    Background: It is well established that biallelic mutations in transmembrane protease, serine 3 (TMPRSS3) cause hearing loss. Currently, there is controversy regarding the audiological outcomes after cochlear implantation (CI) for TMPRSS3-associated hearing loss. This controversy creates confusion among healthcare providers regarding the best treatment options for individuals with TMPRSS3-related hearing loss. Methods: A literature review was performed to identify all published cases of patients with TMPRSS3-associated hearing loss who received a CI. CI outcomes of this cohort were compared with published adult CI cohorts using postoperative consonant-nucleus-consonant (CNC) word performance. TMPRSS3 expression in mouse cochlea and human auditory nerves (HAN) was determined by using hybridisation chain reaction and single-cell RNA-sequencing analysis. Results: In aggregate, 27 patients (30 total CI ears) with TMPRSS3-associated hearing loss treated with CI, and 85% of patients reported favourable outcomes. Postoperative CNC word scores in patients with TMPRSS3-associated hearing loss were not significantly different than those seen in adult CI cohorts (8 studies). Robust Tmprss3 expression occurs throughout the mouse organ of Corti, the spindle and root cells of the lateral wall and faint staining within <5% of the HAN, representing type II spiral ganglion neurons. Adult HAN express negligible levels of TMPRSS3. Conclusion: The clinical features after CI and physiological expression of TMPRSS3 suggest against a major role of TMPRSS3 in auditory neurons.