Gene Therapy Restores Balance and Auditory Functions in a Mouse Model of Usher Syndrome

Abstract

Following the publication of the article, the authors realized that the Whirlin cDNA (NCBI accession no. AY739114) used in the study contains two synonymous variants (Leu476Leu (CTC to CTT), and Thr537Thr (ACA to ACG)) and one non-synonymous variant (Gly550Arg (GGA to AGA)). The authors regret this error. We corrected all three variants to conform to the wild type mouse sequence (accession number AY739114) and repeated the inner ear gene therapy experiments in the whirler mutant mice (Whrn wi/wi ) as published in the original study. The corrected AAV8-whirlin was delivered via the posterior canal approach and caused a partial improvement in the auditory function in the Whrn wi/wi mice (mean ABR thresholds of 97.5 ± 1.64, 81.9 ± 5.08, 95.0 ± 2.67, and 95.7 ± 2.59 at stimulus frequencies of 4 kHz, 8 kHz, 16 kHz, and 32 kHz, respectively, n=5). The magnitudes of ABR threshold improvement are similar to our previously published results (p = 0.27, ANOVA). The corrected AAV8-whirlin delivered via the posterior canal approach also led to an improvement in the vestibular function in the Whrn wi/wi mice, as indicated by a reduction in circling behavior (7.20 ± 0.43 rotations per 2 min). This improvement in vestibular function is also similar to our previously published results (p = 0.41, t-test). Thus, correction of the variants that were present in the original whirlin cDNA did not alter the conclusions of the study.

Advancements and future prospects of adeno-associated virus-mediated gene therapy for sensorineural hearing loss

“…Given that over 50% of gene mutations responsible for hereditary HL affect HCs, gene therapy studies have primarily focused on these sensory cells ( Ahmed et al, 2017 ). Numerous mouse models bearing mutations in genes associated with HCs’ stereocilia, including Myo6 , Tmc1 , Ush1c , Ush1g , Whrn , Lhfpl5 , Pcdh15 , Clrn1 , Klhl18 , and Strc , have shown promising results with the application of AAV-mediated gene therapies ( Askew et al, 2015 ; Chien et al, 2016 ; Shibata et al, 2016 ; Emptoz et al, 2017 ; Geng et al, 2017 ; György et al, 2017 ; Pan et al, 2017 ; Dulon et al, 2018 ; Nist-Lund et al, 2019 ; Yoshimura et al, 2019 ; György et al, 2019a , b ; Yeh et al, 2020 ; Shubina-Oleinik et al, 2021 ; Wu J. et al, 2021 ; Gu et al, 2022 ; Isgrig et al, 2022 ; Liu et al, 2022 ; Xiao et al, 2022 ; Xue et al, 2022 ; Zheng et al, 2022 ). OTOF and VGLUT3 are mainly localized in IHCs and play a significant role in synaptic transmission.…”

Surgical Considerations in Inner Ear Gene Therapy from Human Temporal Bone Anatomy

“…2,3 The widespread prevalence of SNHL, which is increasing with aging populations, highlights the need to develop safe restorative and preventative treatments. [4][5][6][7][8] Local application of drugs to the ear has gained clinical acceptance through transtympanic injection to the middle ear. However, drugs injected into the middle ear may reach the inner ear to variable degrees as the delivery depends on passive diffusion through the oval or round windows or the surrounding bone.…”

“…The most common underlying etiologies are genetic, age‐related, noise‐induced, and drug‐related 2,3 . The widespread prevalence of SNHL, which is increasing with aging populations, highlights the need to develop safe restorative and preventative treatments 4–8 …”