TMPRSS3 expression is limited in spiral ganglion neurons: implication for successful cochlear implantation

Chen, Yuan-Siao; Cabrera, Ernesto; Tucker, Brady J; Shin, Timothy J.; Moawad, Jasmine V; Totten, Douglas J.; Booth, Kevin T.; Nelson, Rick F.

doi:10.1136/jmg-2022-108654

Cited by 10 publications

(10 citation statements)

References 44 publications

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“…39,58 A recent study also showed low TMPRSS3 expression in human auditory neurons. 58 By RNAscope, we found that AAV2 carrying the human TMPRSS3 coding sequence can properly target IHCs, OHCs, and SGNs. The TMPRSS3 transgene expression pattern resembles that of the WT Tmprss3 expression.…”

Section: Discussionmentioning

confidence: 95%

“…In mouse Tmprss3 has been shown to be expressed in hair cells, and other cochlear cell types including the cells in the modiolus region during development. 39,58 A recent study also showed low TMPRSS3 expression in human auditory neurons. 58 By RNAscope, we found that AAV2 carrying the human TMPRSS3 coding sequence can properly target IHCs, OHCs, and SGNs.…”

Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 95%

“…55 The lack of TMPRSS3 has resulted in hair cell death in mouse organoids and ganglion neuron degeneration in vitro . 56,57 Patients with homozygous TMPRSS3 mutations manifest either postlingual progressive hearing loss (DFNB8) or congenital profound hearing loss (DFNB10) (https://hereditaryhearingloss.org/recessive-genes), 39,58 likely due to the nature of the mutations. In TMPRSS3 patients, cochlear implant is a standard form of treatment.…”

Section: Discussionmentioning

confidence: 99%

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Rescue of Auditory Function by a Single Administration of AAV-TMPRSS3Gene Therapy in Aged Mice of Human Recessive Deafness DFNB8

Ergin

Loeb

et al. 2023

Preprint

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Patients with mutations in the TMPRSS3 gene suffer from recessive deafness DFNB8/DFNB10 for whom cochlear implantation is the only treatment option. Poor cochlear implantation outcomes are seen in some patients. To develop biological treatment for TMPRSS3 patients, we generated a knock-in mouse model with a frequent human DFNB8 TMPRSS3 mutation. The Tmprss3A306T/A306T homozygous mice display delayed onset progressive hearing loss similar to human DFNB8 patients. Using AAV2 as a vector to carry a human TMPRSS3 gene, AAV2-hTMPRSS3 injection in the adult knock-in mouse inner ears results in TMPRSS3 expression in the hair cells and the spiral ganglion neurons. A single AAV2-hTMPRSS3 injection in aged Tmprss3A306T/A306T mice leads to sustained rescue of the auditory function, to a level similar to the wildtype mice. AAV2-hTMPRSS3 delivery rescues the hair cells and the spiral ganglions. This is the first study to demonstrate successful gene therapy in an aged mouse model of human genetic deafness. This study lays the foundation to develop AAV2-hTMPRSS3 gene therapy to treat DFNB8 patients, as a standalone therapy or in combination with cochlear implantation.

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

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Rescue of Auditory Function by a Single Administration of AAV-TMPRSS3Gene Therapy in Aged Mice of Human Recessive Deafness DFNB8

Ergin

Loeb

et al. 2023

Preprint

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“…Two recent reports aggregated the results of published CI cases of patients with pathogenic TMPRSS3 variants. CI outcomes were variable with the majority of the studies showing "positive outcomes" (Moon et al 2021) or "favorable outcomes" (Chen et al 2022) relating to an improvement. While "positive outcomes" or "favorable outcomes" are not well defined in the literature, we have calculated quartiles for word recognition score The three quartiles (blue arrows) of cochlear implant performance are defined as the first or lower quartile (Q1; 25th percentile), the second quartile, which is also the median (Q2; 50th percentile), and the third or upper quartile (Q3; 75th percentile).…”

Section: Introductionmentioning

confidence: 99%

Variability in Cochlear Implantation Outcomes in a Large German Cohort With a Genetic Etiology of Hearing Loss

Tropitzsch,

Schade-Mann,

Gamerdinger

et al. 2023

Ear &Amp; Hearing

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Objectives: The variability in outcomes of cochlear implantation is largely unexplained, and clinical factors are not sufficient for predicting performance. Genetic factors have been suggested to impact outcomes, but the clinical and genetic heterogeneity of hereditary hearing loss makes it difficult to determine and interpret postoperative performance. It is hypothesized that genetic mutations that affect the neuronal components of the cochlea and auditory pathway, targeted by the cochlear implant (CI), may lead to poor performance. A large cohort of CI recipients was studied to verify this hypothesis. Design: This study included a large German cohort of CI recipients (n = 123 implanted ears; n = 76 probands) with a definitive genetic etiology of hearing loss according to the American College of Medical Genetics (ACMG)/Association for Molecular Pathology (AMP) guidelines and documented postoperative audiological outcomes. All patients underwent preoperative clinical and audiological examinations. Postoperative CI outcome measures were based on at least 1 year of postoperative audiological follow-up for patients with postlingual hearing loss onset (>6 years) and 5 years for children with congenital or pre/perilingual hearing loss onset (≤6 years). Genetic analysis was performed based on three different methods that included single-gene screening, custom-designed hearing loss gene panel sequencing, targeting known syndromic and nonsyndromic hearing loss genes, and whole-genome sequencing. Results: The genetic diagnosis of the 76 probands in the genetic cohort involved 35 genes and 61 different clinically relevant (pathogenic, likely pathogenic) variants. With regard to implanted ears (n = 123), the six most frequently affected genes affecting nearly one-half of implanted ears were GJB2 (21%; n = 26), TMPRSS3 (7%; n = 9), MYO15A (7%; n = 8), SLC26A4 (5%; n = 6), and LOXHD1 and USH2A (each 4%; n = 5). CI recipients with pathogenic variants that influence the sensory nonneural structures performed at or above the median level of speech performance of all ears at 70% [monosyllable word recognition score in quiet at 65 decibels sound pressure level (SPL)]. When gene expression categories were compared to demographic and clinical categories (total number of compared categories: n = 30), mutations in genes expressed in the spiral ganglion emerged as a significant factor more negatively affecting cochlear implantation outcomes than all clinical parameters. An ANOVA of a reduced set of genetic and clinical categories (n = 10) identified five detrimental factors leading to poorer performance with highly significant effects (p < 0.001), accounting for a total of 11.8% of the observed variance. The single strongest category was neural gene expression accounting for 3.1% of the variance. Conclusions: The analysis of the relationship between the molecular genetic diagnoses of a hereditary etiology of hearing loss and cochlear implantation outcomes in a large German cohort of CI recipients revealed significant variabilities. Poor performance was observed with genetic mutations that affected the neural components of the cochlea, supporting the “spiral ganglion hypothesis.”

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The natural history and genotype–phenotype correlations of TMPRSS3 hearing loss: an international, multi-center, cohort analysis

Colbert,

Lanting,

Smeal

et al. 2024

Hum. Genet.

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TMPRSS3-related hearing loss presents challenges in correlating genotypic variants with clinical phenotypes due to the small sample sizes of previous studies. We conducted a cross-sectional genomics study coupled with retrospective clinical phenotype analysis on 127 individuals. These individuals were from 16 academic medical centers across 6 countries. Key findings revealed 47 unique TMPRSS3 variants with significant differences in hearing thresholds between those with missense variants versus those with loss-of-function genotypes. The hearing loss progression rate for the DFNB8 subtype was 0.3 dB/year. Post-cochlear implantation, an average word recognition score of 76% was observed. Of the 51 individuals with two missense variants, 10 had DFNB10 with profound hearing loss. These 10 all had at least one of 4 TMPRSS3 variants predicted by computational modeling to be damaging to TMPRSS3 structure and function. To our knowledge, this is the largest study of TMPRSS3 genotype–phenotype correlations. We find significant differences in hearing thresholds, hearing loss progression, and age of presentation, by TMPRSS3 genotype and protein domain affected. Most individuals with TMPRSS3 variants perform well on speech recognition tests after cochlear implant, however increased age at implant is associated with worse outcomes. These findings provide insight for genetic counseling and the on-going design of novel therapeutic approaches.

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TMPRSS3 expression is limited in spiral ganglion neurons: implication for successful cochlear implantation

Cited by 10 publications

References 44 publications

Rescue of Auditory Function by a Single Administration of AAV-TMPRSS3Gene Therapy in Aged Mice of Human Recessive Deafness DFNB8

Rescue of Auditory Function by a Single Administration of AAV-TMPRSS3Gene Therapy in Aged Mice of Human Recessive Deafness DFNB8

Variability in Cochlear Implantation Outcomes in a Large German Cohort With a Genetic Etiology of Hearing Loss

The natural history and genotype–phenotype correlations of TMPRSS3 hearing loss: an international, multi-center, cohort analysis

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