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CRISPR-free RNA Base Editing Mediated PTC-readthrough Restores Hearing in Humanized Mice with Otof Nonsense Mutation [PRAISE]

ABSTRACT: 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.

ORGANISM(S): Mus

PROVIDER: GSE262204 | GEO | 2025/10/27

REPOSITORIES: GEO

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Project description:The superior olivary complex (SOC) is an essential auditory brainstem structure involved in sound localization. In order to identify the genetic program underlying its maturation, we profiled the transcriptome of the rat SOC at postnatal days (P)0, P4, P16, and P25, using genome-wide microarrays (41,012 sequences). Differences in gene expression between two consecutive stages were highest between P4 versus P16 (3.6%), but dropped to 0.06% between P16 versus P25. To identify SOC-related genetic programs, we also profiled the brain at P4 and P25. Differentially expressed sequences between SOC and brain almost doubled from P4 (4.4%) to P25 (7.6%). These datademonstrate considerable molecular specification around hearing onset, which is rapidly finalized. Prior to hearing onset, several transcription factors associated with the peripheral auditory system were up-regulated, likely coordinating auditory system development. Additionally, serotonin-related genes and crystalline-gamma subunits were highly expressed. The molecular repertoire of mature neurons was sculpted by SOC-related up- and down-regulation of several protein categories, among which voltage-gated channels and myelination were prominent. Comparison with the brain revealed a significant enrichment of deafness-related oligos in the SOC-related genetic program (26 in the SOC, only 11 in the brain). Furthermore, 29 out of 453 SOC-related oligos mapped within 19 genetic intervals associated with hearing impairment. Together, we identified sequential genetic programs in the SOC, thereby pinpointing candidates which may guide its development and ensure proper function. The enrichment of deafness-related genes in the SOC may have implications for restoring hearing, as central auditory structures might be more severely affected than previously appreciated. This SuperSeries is composed of the SubSeries listed below. The genome wide expression during the postnatal development of the SOC was investigated at four different time points: at postnatal (P) day 0, P4, P16 and P25. Concerning the brain, P4 and P25 were used. Samples were hybridized onto two color platforms. At least 6 up to nine biological replicates per sample were performed.

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CRISPR-free RNA Base Editing Mediated PTC-readthrough Restores Hearing in Humanized Mice with Otof Nonsense Mutation [PRAISE]

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