What is Non-Syndromic Hearing Loss?​​

 

Hearing loss is one of the most common birth defects, with a global incidence of approximately 1.86 per 1,000 newborns. It is widely accepted that over 60% of hearing loss cases are attributable to genetic factors. Hereditary hearing loss can be classified into two types: Syndromic Hearing Loss (SHL) and Non-Syndromic Hearing Loss (NSHL). NSHL is the most common form, accounting for about 70% of all genetic hearing loss cases.

 

NSHL primarily affects the function of the cochlea or the auditory nerve, without involving abnormalities in other organs or systems. The main clinical manifestation is sensorineural hearing loss. Affected individuals may present with hearing impairment at birth, or may experience progressive hearing loss during childhood or adulthood.

 

​Pathogenesis and Gene Therapy​

 

The pathogenesis of NSHL is complex, involving mutations in numerous genes such as mtDNA 12S rRNA, SLC26A4, GJB2, GJB3, and GJB6, and exhibits diverse inheritance patterns, including autosomal recessive, autosomal dominant, X-linked, and mitochondrial inheritance. Known genes associated with NSHL can be categorized by their functions as follows:

 

(1) ​Cytoskeletal Protein-Encoding Genes: Actin and myosin are critical proteins influencing the structure and function of stereocilia. Mutations in genes such as ACTG1and MYO7Acan disrupt actin structure or impair the ATP hydrolysis-driven sliding of myosin along actin filaments, thereby affecting hair bundle motility.

 

(2) ​Cell Junction Protein-Encoding Genes: Cellular junctions in the inner ear are essential for maintaining ionic and voltage gradients of the endolymph and perilymph. Mutations in gap junction protein genes like GJB2and GJB6can disrupt potassium ion recycling, leading to a reduction or loss of the endocochlear potential and ultimately resulting in hair cell death.

 

Mutations in the GJB2gene, which encodes Connexin 26—a protein expressed in cochlear supporting cells and responsible for intercellular communication—account for approximately 10%-25% of NSHL cases. Common GJB2mutations in the Chinese population include c.235delC, c.299_300delAT, c.176_191del16, and c.109G>A.

 

(3) ​Ion Channel Protein-Encoding Genes: Genes encoding ion channels related to hearing loss, such as SLC26A4and TMC1, play vital roles in maintaining ionic homeostasis and voltage stability in the inner ear fluids.

 

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

 

(5) ​Hair Cell Synaptic Protein-Encoding Genes:Mutations in the OTOFgene disrupt the function of otoferlin, leading to auditory neuropathy. Otoferlin, encoded by OTOF, is a calcium-sensing protein specific to the ribbon synapses of cochlear hair cells; it mediates synaptic vesicle exocytosis, fusion, and replenishment. OTOFmutations cause autosomal recessive deafness DFNB9, typically characterized by prelingual, moderate-to-profound hearing loss, with some patients exhibiting temperature-sensitive hearing loss.

 

The SLC17A8gene encodes vesicular glutamate transporter 3 (VGLUT3), which mediates glutamate uptake into synaptic vesicles at inner hair cell ribbon synapses. It is crucial for the development and encoding function of the auditory pathway. Mutations lead to insufficient glutamate levels in the synaptic cleft, impaired action potential generation, and failure of auditory signal transmission, causing autosomal dominant non-syndromic hearing loss DFNA25, clinically presenting as progressive high-frequency hearing loss.

 

(6) ​Transcription Factor-Encoding Genes: Genes such as POU3F4and POU4F3encode POU-domain transcription factors that play critical roles in inner ear development. Additionally, numerous other genes are involved in ciliary function, cellular homeostasis, and RNA products crucial for inner ear function (e.g., mitochondrial 12S rRNA encoded by the MT-RNR1gene, microRNA-96 encoded by MIR96).

 

​Gene Therapy: A Promising Frontier​

 

The rapid advancement of gene therapy technologies has brought new hope for treating rare diseases. Gene therapy addresses the genetic root cause by repairing or replacing defective genes. The primary strategies include gene replacement, gene suppression, and gene editing. Importantly, the choice of strategy depends on the specific pathogenic mechanism of the monogenic disease. With continuous innovation in genetic manipulation tools, gene therapy for hereditary hearing loss has achieved remarkable progress in recent years.

 

In preclinical studies, over 40 investigations have successfully restored hearing in animal models involving more than 20 distinct deafness-related genes using gene therapy strategies. Globally, three clinical trials for genetic hearing loss have been approved, including a project led by Professor Shu Yilai from the Eye & ENT Hospital of Fudan University, which completed the world's first in vivo gene therapy administration for a patient with OTOF-related hearing loss. These advances offer significant promise for the treatment of NSHL, suggesting that gene therapy may become an effective treatment modality in the future.

 

​Animal Models in Research​

 

While gene therapy offers immense promise, its development and validation rely heavily on animal models. MingCeler Biotech, leveraging its proprietary TurboMice™ platform, has developed multiple rare disease mouse models. The TurboMice™ technology overcomes challenges such as long modeling cycles and low success rates for complex models, enabling precise editing at virtually any target genomic locus and allowing for the generation of complete homozygous gene-edited mouse models directly from embryonic stem cells in as little as two months.

 

MingCeler Biotech offers custom services for developing various hearing loss mouse models, such as Otof ⁻/⁻ mice, Vglut3knockout mice, and Tmc1mutant mice. We welcome inquiries regarding your specific research requirements.