Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1194749 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Hearing loss is one of the most prevalent sensory disorders, but no commercial biological treatments are currently available. Here, we identify an East Asia-specific founder mutation, the homozygous c.220C>T mutation in MPZL2, that contributes to a significant proportion of hereditary deafness cases in our cohort study. We find that the disease-causing mutation can be targetable by adenine base editors (ABEs) that enable A·T-to-G·C base corrections without DNA double-strand breaks. To demonstrate this, we develop a humanized mouse model (hMPZL2Q74X/Q74X) that recapitulates human MPZL2 deafness and leads to progressive hearing loss. A PAM-flexible ABE variant with reduced bystander and off-target effects (ABE8eWQ-SpRY:sgRNA3) is packaged in dual adeno-associated viruses (AAVs) and injected into the inner ear of hMPZL2Q74X/Q74X mice and effectively corrects the mutation. This treatment significantly restores hearing function, improves inner ear structural integrity, and reverses altered gene expression. Base editing may hold therapeutic potential for hereditary deafness, including most cases of MPZL2 deafness.
2025-07-01 | GSE299064 | GEO
Project description:Deafness is the most common form of sensory impairment in humans and frequently caused by defects in hair cells of the inner ear. Here we demonstrate that in a mouse model for recessive non-syndromic deafness (DFNB6), inactivation of Tmie in hair cells disrupts gene expression in the neurons that innervate them. This includes genes regulating axonal pathfinding and synaptogenesis, two processes that are disrupted in the inner ear of the mutant mice. Similar defects are observed in mouse models for deafness caused by mutations in other genes with primary functions in hair cells. Gene therapy targeting hair cells restores hearing and inner ear circuitry in DFNB6 model mice. We conclude that hair cell function is crucial for the establishment of peripheral auditory circuitry. Treatment modalities for deafness thus need to consider restoration of the function of both hair cells and neurons, even when the primary defect occurs in hair cells.
2024-11-10 | GSE281207 | GEO
Project description:Today, the gene editing for hereditary deafness is becoming a promising field with global interest. Among them, AAV-mediated otoferlin overexpression is undoubtedly the most successful representative of deaf-related gene therapy. However, it remains challenging to realize physiological, endogenous pattern of otoferlin expression. Here, we firstly generated a humanized homology Otof c.1315C>T (p.R439X), equivalent to OTOF c.1273C>T (p.R425X) identified in human with profound hearing loss, nonsense mutation-caused deaf mice model. We then delivered the ‘RESTART v3’ system, which is a CRISPR-free RNA base editor for nonsense mutation suppression, into the cochlea of the mice model. We accomplished a physiological manner of otoferlin expression; moreover, the edited premature termination codon is precisely reversed back to the original amino acid. Using multiple assays to estimate hearing restoration, we identified a significant reduced thresholds of auditory brain response (ABR) and statistical enhanced amplitudes of behavioral auditory startle reflex (ASR) in the treated mice with the RNA editing system. Thus, our study presented a successful CRISPR-free RNA editing approach to significantly restore hereditary deafness carrying humanized Otof c.1315C>T (p.R439X) non-sense mutation, providing a great promise for future clinical translation.
2025-10-27 | GSE262204 | GEO
Project description:Today, the gene editing for hereditary deafness is becoming a promising field with global interest. Among them, AAV-mediated otoferlin overexpression is undoubtedly the most successful representative of deaf-related gene therapy. However, it remains challenging to realize physiological, endogenous pattern of otoferlin expression. Here, we firstly generated a humanized homology Otof c.1315C>T (p.R439X), equivalent to OTOF c.1273C>T (p.R425X) identified in human with profound hearing loss, nonsense mutation-caused deaf mice model. We then delivered the ‘RESTART v3’ system, which is a CRISPR-free RNA base editor for nonsense mutation suppression, into the cochlea of the mice model. We accomplished a physiological manner of otoferlin expression; moreover, the edited premature termination codon is precisely reversed back to the original amino acid. Using multiple assays to estimate hearing restoration, we identified a significant reduced thresholds of auditory brain response (ABR) and statistical enhanced amplitudes of behavioral auditory startle reflex (ASR) in the treated mice with the RNA editing system. Thus, our study presented a successful CRISPR-free RNA editing approach to significantly restore hereditary deafness carrying humanized Otof c.1315C>T (p.R439X) non-sense mutation, providing a great promise for future clinical translation.
2025-10-27 | GSE262206 | GEO
Project description:Today, the gene editing for hereditary deafness is becoming a promising field with global interest. Among them, AAV-mediated otoferlin overexpression is undoubtedly the most successful representative of deaf-related gene therapy. However, it remains challenging to realize physiological, endogenous pattern of otoferlin expression. Here, we firstly generated a humanized homology Otof c.1315C>T (p.R439X), equivalent to OTOF c.1273C>T (p.R425X) identified in human with profound hearing loss, nonsense mutation-caused deaf mice model. We then delivered the ‘RESTART v3’ system, which is a CRISPR-free RNA base editor for nonsense mutation suppression, into the cochlea of the mice model. We accomplished a physiological manner of otoferlin expression; moreover, the edited premature termination codon is precisely reversed back to the original amino acid. Using multiple assays to estimate hearing restoration, we identified a significant reduced thresholds of auditory brain response (ABR) and statistical enhanced amplitudes of behavioral auditory startle reflex (ASR) in the treated mice with the RNA editing system. Thus, our study presented a successful CRISPR-free RNA editing approach to significantly restore hereditary deafness carrying humanized Otof c.1315C>T (p.R439X) non-sense mutation, providing a great promise for future clinical translation.
2025-10-27 | GSE262205 | GEO