What is Non-Syndromic Deafness?
 

Deafness is the most common birth defect, with a global incidence of hearing loss in newborns of 1.86‰. Currently, it is widely accepted that over 60% of deafness cases are caused by genetic factors. Hereditary deafness can be classified into two types: syndromic hearing loss (SHL) and non-syndromic hearing loss (NSHL), which is the most common form of hereditary deafness, accounting for approximately 70% of all cases.

Non-syndromic deafness primarily affects the function of the cochlea or auditory nerve without involving other tissues or organs. The main clinical manifestation is sensorineural hearing loss. Patients may exhibit hearing impairment at birth or gradually develop hearing loss during childhood or adulthood.
 

Pathogenesis and Gene Therapy
 

The pathogenesis of non-syndromic deafness is complex, involving multiple gene mutations such as mtDNA 12S rRNA, SLC26A4, GJB2, GJB3, GJB6, and others. The inheritance patterns are diverse, including autosomal recessive, autosomal dominant, X-linked, and mitochondrial inheritance. Known genes associated with non-syndromic deafness can be categorized based on their functions:

(1) Cytoskeletal Protein-Encoding Genes: Actin and myosin are crucial proteins that affect the structure and function of stereocilia. Mutations in related genes such as ACTG1 and MYO7A can alter actin structure and affect myosin's ATP hydrolysis, which provides energy for sliding along actin filaments, ultimately impacting ciliary movement.

(2) Intercellular Junction Protein-Encoding Genes: Intercellular junctions in the inner ear play a vital role in maintaining ion and voltage balance between endolymph and perilymph. Mutations in gap junction protein genes such as GJB2 and GJB6 can disrupt potassium ion circulation, leading to reduced or abolished endocochlear potential and ultimately causing hair cell death.

Research reports indicate that GJB2 gene mutations account for approximately 10%-25% of non-syndromic deafness cases. This gene encodes connexin 26, which is expressed in cochlear supporting cells and is responsible for intercellular signal transmission. Common GJB2 gene mutation types in China include: c.235delC, c.299-300delAT, c.176-191del16, c.109G>A, and others.

(3) Ion Channel Protein-Encoding Genes: Ion channel protein-encoding genes associated with hearing loss include SLC26A4, TMC1, and others, which are essential for maintaining ion and voltage stability in the inner ear fluids.

(4) Extracellular Matrix Protein-Encoding Genes: For example, the TECTA gene encodes tectorin, a major component of the tectorial membrane.

(5) Hair Cell Synaptic Function Proteins: OTOF gene mutations affect the normal function of hair cell synaptic binding proteins, leading to auditory neuropathy. Otoferlin, encoded by the OTOF gene, is a specific calcium-binding protein at cochlear ribbon synapses. It functions as a calcium concentration sensor, driving vesicle exocytosis, fusion, and replenishment of vesicles at the active zone of ribbon synapses. OTOF gene mutations cause autosomal recessive deafness DFNB9. Patients typically present with prelingual deafness, moderate to severe hearing loss, and some exhibit temperature sensitivity.

The SLC17A8 gene encodes Vglut3 protein, which mediates glutamate vesicle uptake at inner hair cell ribbon synapses. It plays a crucial role in the development and encoding function of the auditory pathway. Mutations lead to insufficient glutamate levels in the synaptic cleft, making it difficult to generate action potentials and transmit auditory signals, causing autosomal dominant non-syndromic deafness DFNA25. The clinical manifestation is progressive high-frequency hearing loss.

(6)  Transcription Factor-Encoding Genes: Such as POU3F4 and POU4F3, which encode two POU domain transcription family proteins that play important roles in inner ear development. Additionally, there are numerous genes related to ciliary function and cellular homeostasis, as well as genes encoding RNA products closely associated with inner ear function, such as 12S rRNA, MIR96 (encoding mitochondrial 12S rRNA and miRNA96).

(Source: SCIENCE)

The rapid development of gene therapy technology has brought new hope for the treatment of rare diseases. Gene therapy directly targets the genetic root of diseases by repairing or replacing defective genes. The main strategies for gene therapy include three approaches: gene replacement, gene suppression, and gene editing. Importantly, different strategies are applicable to different monogenic diseases based on their pathogenic mechanisms. With the continuous iteration and updating of gene manipulation tools, significant progress has been made in the gene therapy of hereditary deafness in recent years.

In preclinical studies, over 40 studies have successfully corrected hearing in more than 20 deafness gene-related animal models using gene therapy strategies. Globally, three clinical trials for gene therapy of hereditary deafness have been approved, including a project led by Professor Shu Yilai's team at Fudan University Eye & ENT Hospital, which completed the world's first in vivo administration to an OTOF hereditary deafness patient. These advances bring new hope for the treatment of non-syndromic deafness, and gene therapy is expected to become an effective treatment for non-syndromic deafness in the future.
 

(Source: SCIENCE)

MingCeler Biotech Facilitates Gene Therapy
 

Gene therapy offers hope for rare diseases, but its development and validation are inseparable from animal model support. Leveraging its self-developed TurboMice™ technology, MingCeler Biotech has developed multiple rare disease mouse models. The TurboMice™ technology overcomes the challenges of long modeling cycles and low success rates for complex models. It enables editing at virtually any target gene locus and can generate complete homozygous gene-edited mouse models directly from embryonic stem cells in as little as 2 months.

MingCeler Biotech can customize various deafness mouse models according to client needs, such as Otof-/- mice, Vglut3 knockout mice, Tmc1 gene mutation mice, and others. We welcome inquiries!

 

References:

[1] Bu Yunfei, Lü Xiaoguang, Wang Yang, et al. Analysis of Pathogenic Gene Mutation Sites in 22 Cases of Non-syndromic Deafness [J]. Journal of Nanjing Medical University, 2010, 30(3): 390-393.

[2] Jiang L, Wang D, He Y, Shu Y. Advances in gene therapy hold promise for treating hereditary hearing loss. Mol Ther. 2023 Apr 5;31(4):934-950. doi: 10.1016/j.ymthe.2023.02.001. IF: 12.4 Q1. Epub 2023 Feb 8. PMID: 36755494; PMCID: PMC10124073.

[3] Sun Yilin, Jin Chenxi, Feng Baoyi, et al. Current Status of Gene Therapy for Auditory Neuropathy [J]. Chinese Journal of Otorhinolaryngology Head and Neck Surgery, 2024, 59(5): 510-518. DOI: 10.3760/cma.j.cn115330-20231029-00177.

[4] Chinese Journal of Medical Genetics, 2020, 37(03): 269-276. DOI: 10.3760/cma.j.issn.1003-9406.2020.03.008.

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