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Gene editing in a Myo6 semi-dominant mouse model rescues auditory function
Yuanyuan Xue1, Xinde Hu2, Daqi Wang1
1ENT Institute and Department of Otorhinolaryngology, Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200031, China; Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China; NHC Key Laboratory of Hearing Medicine, Fudan University, Shanghai 200031, China.
Gene therapy using adeno-associated virus (AAV) delivered Staphylococcus aureus Cas9 (SaCas9-KKH) to correct a Myosin VI (MYO6) gene mutation. This approach successfully ameliorated hearing loss in a mouse model, offering hope for treating genetic hearing disorders.
Area of Science:
- Genetics
- Molecular Biology
- Otolaryngology
Background:
- Myosin VI (MYO6) is crucial for auditory and vestibular function.
- Pathogenic variants in the MYO6 gene cause hereditary hearing loss.
- Current treatments for MYO6-related hearing loss are limited.
Purpose of the Study:
- To investigate the efficacy of adeno-associated virus (AAV)-PHP.eB vector-mediated in vivo delivery of Staphylococcus aureus Cas9 (SaCas9-KKH)-single-guide RNA (sgRNA) complexes for ameliorating hearing loss in a Myo6 mouse model.
- To evaluate the potential of in vivo genome editing as a therapeutic strategy for MYO6-associated hearing loss.
Main Methods:
- Utilized a Myo6 WT/C442Y mouse model mimicking human hearing loss phenotypes.
- Administered AAV-PHP.eB vectors carrying SaCas9-KKH and sgRNA targeting the MYO6 gene.
- Assessed in vivo editing efficiency, auditory function (ABR, DPOAE), hair cell morphology, and calcium levels.
Main Results:
- Achieved an average in vivo editing efficiency of 4.05% for the Myo6 C442Y mutation, approximately 17-fold higher than for wild-type alleles.
- Observed rescue of auditory function up to 5 months post-injection.
- Demonstrated shorter ABR wave I latencies, lower DPOAE thresholds, increased cell survival, improved hair bundle morphology, and restored calcium levels in treated ears.
Conclusions:
- AAV-mediated in vivo genome editing with SaCas9-KKH effectively ameliorated hearing loss in a mouse model of MYO6-related semi-dominant hearing loss.
- This study provides a preclinical reference for using in vivo genome editing to treat semi-dominant forms of hearing loss and other genetic disorders.
