Clinical gene therapy restores hearing: a paradigm shift.

Recent breakthroughs in gene therapy for autosomal recessive deafness 9 (DFNB9) caused by OTOF mutations have transformed treatment paradigms for hereditary hearing loss (HHL). To date, eight clinical trials targeting DFNB9 have been registered in 51 centers across eight countries, demonstrating the rapid progress of gene therapy in auditory medicine. These pioneering studies establish the framework for the clinical translation of gene therapy targeting HHL.

Erratum: Preclinical evaluation of the efficacy and safety of AAV1-hOTOF in mice and nonhuman primates.

[This corrects the article DOI: 10.1016/j.omtm.

Size-dependent performance of white light LEDs for intelligent vehicle lighting and communication.

In this paper, size-dependent illumination performances of white light micro light-emitting diodes (LEDs) and a visible light communication (VLC) system were demonstrated. The white light LEDs from 10 m to 200 m were prepared by exciting three phosphors with blue LEDs and the current density versus voltage, luminous efficiency, and electroluminescence (EL) spectra were measured. At 300 A/cm, the luminous efficiency of the 60 m white LED was 1.

Gene Therapy vs Cochlear Implantation in Restoring Hearing Function and Speech Perception for Individuals With Congenital Deafness.

Importance: OTOF gene therapy (GT) has been shown to improve hearing and speech. The efficacy of GT remains to be compared against cochlear implantation (CI), the current gold standard for congenital deafness.

Objective: To evaluate treatment outcomes in auditory and speech perception between patients with congenital deafness treated with GT, CI, or both.

Audiological characteristics following gene therapy in patients with autosomal recessive deafness 9.

Background: Gene therapy shows promising potential for patients with autosomal recessive deafness 9 (DFNB9), with ongoing clinical trials (ChiCTR2200063181). A deeper understanding of changes in audiological characteristics is crucial for optimizing the monitoring and evaluation of patients' recovery post-treatment.

Methods: Audiological data were collected from 10 DFNB9 patients who underwent gene therapy, including auditory brain stem response (ABR), auditory steady-state response (ASSR), distortion product otoacoustic emission (DPOAE), and pure-tone audiometry (PTA) tests.

Preliminary evidence for enhanced auditory cortex activation and mental development after gene therapy in children with autosomal recessive deafness 9.

Individuals with congenital deafness that have received gene therapy represent a unique group who experience hearing recovery and speech development. However, it is unclear how hearing-related cortex changes because of gene therapy. Here we study neural processing in ten patients using functional near-infrared spectroscopy and electroencephalography during a six-month follow-up period.

Bilateral gene therapy in children with autosomal recessive deafness 9: single-arm trial results.

Gene therapy is a promising approach for hereditary deafness. We recently showed that unilateral AAV1-hOTOF gene therapy with dual adeno-associated virus (AAV) serotype 1 carrying human OTOF transgene is safe and associated with functional improvements in patients with autosomal recessive deafness 9 (DFNB9). The protocol was subsequently amended and approved to allow bilateral gene therapy administration.

Engineering of the AAV-Compatible Hair Cell-Specific Small-Size Myo15 Promoter for Gene Therapy in the Inner Ear.

Adeno-associated virus (AAV)-mediated gene therapy is widely applied to treat numerous hereditary diseases in animal models and humans. The specific expression of AAV-delivered transgenes driven by cell type-specific promoters should further increase the safety of gene therapy. However, current methods for screening cell type-specific promoters are labor-intensive and time-consuming.

Hair cell-specific Myo15 promoter-mediated gene therapy rescues hearing in DFNB9 mouse model.

Adeno-associated viral (AAV) vectors are increasingly used as vehicles for gene delivery to treat hearing loss. However, lack of specificity of the transgene expression may lead to overexpression of the transgene in nontarget tissues. In this study, we evaluated the expression efficiency and specificity of transgene delivered by AAV-PHP.

AAV1-hOTOF gene therapy for autosomal recessive deafness 9: a single-arm trial.

Background: Autosomal recessive deafness 9, caused by mutations of the OTOF gene, is characterised by congenital or prelingual, severe-to-complete, bilateral hearing loss. However, no pharmacological treatment is currently available for congenital deafness. In this Article, we report the safety and efficacy of gene therapy with an adeno-associated virus (AAV) serotype 1 carrying a human OTOF transgene (AAV1-hOTOF) as a treatment for children with autosomal recessive deafness 9.

Mechanisms and otoprotective strategies of programmed cell death on aminoglycoside-induced ototoxicity.

Aminoglycosides are commonly used for the treatment of life-threatening bacterial infections, however, aminoglycosides may cause irreversible hearing loss with a long-term clinical therapy. The mechanism and prevention of the ototoxicity of aminoglycosides are still limited although amounts of studies explored widely. Specifically, advancements in programmed cell death (PCD) provide more new perspectives.

The pathogenesis of common Gjb2 mutations associated with human hereditary deafness in mice.

Mutations in GJB2 (Gap junction protein beta 2) are the most common genetic cause of non-syndromic hereditary deafness in humans, especially the 35delG and 235delC mutations. Owing to the homozygous lethality of Gjb2 mutations in mice, there are currently no perfect mouse models carrying Gjb2 mutations derived from patients for mimicking human hereditary deafness and for unveiling the pathogenesis of the disease. Here, we successfully constructed heterozygous Gjb2 and Gjb2 mutant mice through advanced androgenic haploid embryonic stem cell (AG-haESC)-mediated semi-cloning technology, and these mice showed normal hearing at postnatal day (P) 28.

Advances in gene therapy hold promise for treating hereditary hearing loss.

Gene therapy focuses on genetic modification to produce therapeutic effects or treat diseases by repairing or reconstructing genetic material, thus being expected to be the most promising therapeutic strategy for genetic disorders. Due to the growing attention to hearing impairment, an increasing amount of research is attempting to utilize gene therapy for hereditary hearing loss (HHL), an important monogenic disease and the most common type of congenital deafness. Several gene therapy clinical trials for HHL have recently been approved, and, additionally, CRISPR-Cas tools have been attempted for HHL treatment.

Approaches and Vectors for Efficient Cochlear Gene Transfer in Adult Mouse Models.

Inner ear gene therapy using adeno-associated viral vectors (AAVs) in neonatal mice can alleviate hearing loss in mouse models of deafness. However, efficient and safe transgene delivery to the adult mouse cochlea is critical for the effectiveness of AAV-mediated therapy. Here, we examined three gene delivery approaches including posterior semicircular canal (PSCC) canalostomy, round window membrane (RWM) injection, and tubing-RWM+PSCC (t-RP) in adult mice.

Hearing of Otof-deficient mice restored by trans-splicing of N- and C-terminal otoferlin.

Mutations to the OTOF gene are among the most common reasons for auditory neuropathy. Although cochlear implants are often effective in restoring sound transduction, there are currently no biological treatments for individuals with variants of OTOF. Previous studies have reported the rescue of hearing in DFNB9 mice using OTOF gene replacement although the efficacy needs improvement.

Precise detection of CRISPR-Cas9 editing in hair cells in the treatment of autosomal dominant hearing loss.

Gene therapy would benefit from the effective editing of targeted cells with CRISPR-Cas9 tools. However, it is difficult to precisely assess the editing performance because the tissues contain many non-targeted cells, which is one of the major barriers to clinical translation. Here, in the ; mice, recapitulating a novel mutation we identified in a hereditary hearing loss pedigree, the high-efficiency editing of CRISPR-Cas9 in hair cells (34.

Rescue of mis-splicing of a common mutant associated with sensorineural hearing loss by antisense oligonucleotides.

A wide spectrum of mutations causes Pendred syndrome and enlarged vestibular aqueduct, both associated with sensorineural hearing loss (SNHL). A splice-site mutation, c.919-2A>G (A-2G), which is common in Asian populations, impairs the 3' splice site of intron 7, resulting in exon 8 skipping during pre-mRNA splicing and a subsequent frameshift that creates a premature termination codon in the following exon.

Preventing autosomal-dominant hearing loss in Bth mice with CRISPR/CasRx-based RNA editing.

CRISPR/RfxCas13d (CasRx) editing system can specifically and precisely cleave single-strand RNAs, which is a promising treatment for various disorders by downregulation of related gene expression. Here, we tested this RNA-editing approach on Beethoven (Bth) mice, an animal model for human DFNA36 due to a point mutation in Tmc1. We first screened 30 sgRNAs in cell cultures and found that CasRx with sgRNA3 reduced the Tmc1 transcript by 90.