The study of sensorineural deafness is a top priority in the field of otology. Strictly speaking, sensorineural deafness can be divided into sensorineural and neural in terms of the site of the lesion. Sensorineural deafness can be classified as congenital or acquired from the time of occurrence. Congenital sensorineural deafness can be divided into genetic deafness and environmental deafness (viral infection during pregnancy, etc.), while acquired sensorineural deafness includes sudden deafness, noise deafness, senile deafness, drug deafness, etc. Auditory neuropathy belongs to the category of neurological deafness. Currently, the clinical treatment of severe and very severe sensorineural deafness relies heavily on cochlear implants, which are expensive and beyond the means of most deaf patients and their families. Therefore, the effective prevention and low-cost treatment of sensorineural deafness has been an unsolved clinical problem in otolaryngology for many years, and strengthening research on the prevention and treatment of sensorineural deafness is an effective way to solve this problem. In the last decade or so, basic research and interventional treatment of sensorineural deafness have made substantial progress under the themes of inheritance, innovation and development, and are expected to make new breakthroughs in early diagnosis, treatment and prevention. In terms of diagnosis, the genetic diagnosis of deafness has clarified the cause for more than 30% of Chinese deaf people; in terms of prevention and intervention, the goal of overall reduction of deafness incidence is gradually achieved by using premarital counseling and prenatal diagnosis, and the goal of early detection is achieved by combining newborn hearing screening with simultaneous genetic screening; in terms of treatment, the research of hair cell regeneration drugs in the research of new biological technology is expected to overcome the difficulty of sensorineural In terms of treatment, the research of hair cell regeneration drugs in new biological technology is expected to overcome the difficulty of drug treatment for sensorineural deafness; to accelerate the research and development of localized cochlear implant and base construction to achieve the goal of healthy hearing for all. However, there are still many problems to be solved in order to achieve the above breakthroughs, such as what are the reasons for the high prevalence of deafness in China, what is the load of genetic factors in the Chinese population, what is the mechanism of deafness, what is the genetic susceptibility of senile deafness, how to protect against noise deafness, what is the molecular mechanism of deafness in sudden deafness and auditory neuropathy, how to develop inexpensive and efficient detection instruments and methods to How to improve the hearing screening rate in rural areas, how to carry out early intervention, how to develop new therapeutic tools and practical rehabilitation equipment, how to establish a defensive early warning system to reduce the overall incidence of deafness, and so on. This series of problems requires multidisciplinary support and collaboration among otolaryngology, neurobiology, hearing and speech rehabilitation, genetics, and biomedical engineering to solve. Molecular epidemiological study of sensorineural deafness The second sample survey of disabled people in China (2006) showed that the total number of disabled people in China is 82.96 million, among which, 27.8 million people have hearing and speech disabilities, accounting for 27% of the total number of disabled people, while the number of deaf children under 7 years old is up to 800,000 and continues to grow at a rate of 30,000 deaf children per year [1]. Since 2003, a molecular epidemiological survey of the deaf population was conducted in China through the established network of genetic resources collection for sensorineural deafness. The study revealed the etiology of deafness in the Chinese population: genetic factors account for about 55%; unknown etiology (environmental or other causes) accounts for 45% [2]. In China, GJB2 mutation is the most common cause of deafness, with a mutation detection rate of 21% and a definite rate of 15% of deafness caused by mutations in this gene; SLC26A4 mutation is another common cause of deafness, with a mutation detection rate of at least 15% and a definite rate of 12% of deafness caused by mutations in this gene [3]; A1555G mutation in the mitochondrial 12S rRNA gene and C1494T mutations are common maternally inherited drug-induced deafness-causing mutations in the Chinese deaf population, with a detection rate of 4.4% for these two mutations [4]. That is, on average, 40% of deafness onset in China is associated with these three mutations, and 31% of the Chinese deaf population can be definitively diagnosed by screening for common deafness genes. The fact that a high percentage of deafness is caused by mutations in GJB2, SLC26A4 and mitochondrial genes in Chinese deaf people has given rise to new ideas and methods for deafness prevention and an urgent need for the establishment of a standardized deafness genetic diagnosis network. Research on the molecular genetic mechanism of sensorineural deafness In 1998, academician Jiahui Xia cloned the first deafness-related gene in China, achieving zero breakthrough in local cloning of deafness genes and pioneering the research on deafness gene cloning in China [5]. 2004, Chinese scholars discovered for the first time internationally that homozygous mutations in mitochondrial 12SrRNA C1494T are the cause of deafness in family members exposed to aminoglycosides The cause of severe deafness occurred, and a new molecular mechanism of mitochondrial maternally inherited 12SrRNA C1494T mutation causing deafness was discovered and elucidated [6,7]. Using gene location linkage analysis and candidate gene mutation screening techniques, two X-linked families with profound deafness were localized on the X chromosome, and new mutations in the causative gene POU3F4 [8] and the causative mutation in the PRPS1 gene were identified [9]; a Chinese family with auditory neuropathy was localized within the X chromosome Xq23C27.3 region and named the AUNX1 locus [10]. . A rare Chinese deafness family line was identified in the collected genetic resources, and the concept of Y-linked inheritance was proposed, and this family line was localized on the Y chromosome and named the DFNY1 locus [11]. Six autosomal dominantly inherited late-onset hearing loss family lines were localized on different chromosomes by a linkage analysis method, and in two of them, novel deafness-causing mutations in the COCH and DFNA5 genes were identified in the Chinese population [12,13]. Genomic studies of hereditary sensorineural deafness, despite the many opportunities, also face serious challenges. The diversity and heterogeneity of deafness phenotypes and the current limited scientific development cannot yet explain the true molecular pathology of hearing loss caused by mutations in auditory genes. The same GJB2 mutation that causes profound hearing loss can be found in patients with a single heterozygous mutation, but whose father or mother also carries this mutation have perfectly normal hearing; the same enlarged vestibular aqueduct can be found in a Chinese population with more than 100 mutant forms, and the periodic clinical phenotypes seem to be difficult to identify the differences. In late-onset dominant genetic hearing loss, patients carry the disease-causing mutation at birth but do not develop hearing problems early on but notice a gradual decline in hearing in the first or second or third decade. How the hearing gene network interacts due to environmental influences, DNA methylation and the role of modifier genes remains a mystery. There are currently estimated to be about 250-300 hearing-related genes, but only about 70 clones (including syndromic deafness), and many causative genes for deafness phenotypes are not known. Examples include genetic susceptibility to noise and age-related hearing loss, unexplained delayed hearing loss, and genes related to the auditory pathway of central hearing loss, among others. Completed haplotype maps of the human genome will likely provide powerful tools for these studies, but a long time is still needed to decipher the molecular pathogenesis of the auditory system. More expectations are placed on functional gene studies in mouse models, but in no way can the expression and functional state of mouse genes replace the mechanisms of the auditory system in humans in vivo, so many challenges remain. Auditory neurobiological research The application of new biological technologies has promoted basic and clinical research on sensorineural deafness. New advances have also been made in hair cell regeneration research. We know that a variety of factors such as excessive acoustic stimulation, aging, ototoxic drugs, infections and autoimmune diseases can trigger irreversible damage to cochlear hair cells and auditory neurons, leading to permanent sensorineural deafness. The most critical technology for the ultimate treatment of sensorineural deafness is hair cell regeneration, and the most important thing to achieve clinical application is the development of a product with clinical application prospects – an efficient and safe gene vector. In 2003, Chinese scholars such as Huawei Li reported a new discovery in stem cell research: multipotent stem cells that can differentiate into hair cells and precursor cells can be used to treat deafness. In 2003, Chinese scholars such as Li Huawei reported a new discovery in stem cell research: pluripotent stem cells that can differentiate into precursor cells [16], a discovery that brings light to the treatment of sensorineural deafness through hair cell regeneration. These exciting results give us a bright future for gene therapy of sensorineural deafness and confidence in the treatment of sensorineural deafness. The functional study of sensorineural deafness genes is an important development direction for future sensorineural deafness intervention, and gene knockout is a new biological technique that has been developed and matured in recent years. Using established animal models of sensorineural deafness caused by gene defects to understand the effects of gene inactivation on development, growth, aging, and structural functions of organs, tissues, and cells, and conducting extensive hearing function and inner ear morphology studies on smad5 knockout mice, we found that gene defects can cause severe hearing impairment in mice, and the inner ear auditory organs including hair cells, supporting cells, and spiral The gene defect was found to cause severe hearing impairment and varying degrees of damage to the inner ear auditory organs including hair cells, supporting cells and spiral ganglia [17]. This study has important implications for the study of auditory gene function and the molecular mechanisms of sensorineural deafness, and can be used as a new strategy for the study of sensorineural deafness genes. Gene therapy for sensorineural deafness The inner ear has several unique advantages as a more ideal model for gene therapy: first, the relatively unique anatomy of the inner ear can greatly reduce the side effects caused by gene infection of other tissues, and the concentration and dose of the therapeutic gene are easy to grasp, making it ideal for in vivo studies. Second, there are many technical means to detect the function of various cells in the inner ear to assess the effectiveness and safety of inner ear gene therapy in real time, such as cochlear microphonic potentials and otoacoustic emissions to assess the degree of damage to outer hair cells, compound action potentials to assess the function of inner hair cells, and single cell recordings to assess the function of spiral ganglion cells, and intracochlear potentials to monitor the state of lymphatic ion homeostasis in the cochlea . Once again, there are many gene options available for inner ear gene therapy. More than 90 genes are known to be involved in inner ear function and development, and neurotrophic factors are very good choices for inner ear gene therapy. Research on inner ear gene therapy began in 1996, and the exploration of inner ear gene therapy in the last decade has focused on the following areas: prevention of hair cell death; introduction and regulation of therapeutic gene expression; inhibition of the effects of negative regulatory factors; and stem cell gene therapy [18]. Gene therapy research in the inner ear has progressed significantly in the last five years, and improvements in the introduction method have been able to protect the function of the inner ear intact, and gene therapy can alter the inner ear cell microenvironment and cell phenotype. These phenomena observed in experimental studies have laid the foundation for a new inner ear therapeutics, and the key steps towards the eventual use of gene therapy techniques for deafness treatment have now been successful; viral and non-viral vectors have been shown to introduce and express exogenous genes into the peripheral auditory system. Future more refined work will involve the development of novel chimeric vectors that integrate the high infectivity and stability of viral vectors with the safety of liposomes; gene introduction will also be preferred to methods that minimize cochlear tissue and hearing damage, such as microinjection or round window membrane introduction of vectors; and local and long-range spread of therapeutic agents will be monitored and minimized. The major efforts at this stage of research exploring gene therapy for deafness have focused on genetic approaches to fill in key missing components in the inner ear, and many efforts have failed, with results in this area falling far short of our expectations. Comparatively, antisense RNA or RNA interference technology has shown better potential in gene therapy for deafness, but there are still many obstacles to the clinical application of RNA interference technology, such as suitable and effective introduction methods, consistent and stable silencing of pathogenic gene expression and counteracting the response to interferon. In conclusion, modification of negative regulatory genes and cell cycle genes through improved introduction methods will help to promote the growth of new hair cells. With a deeper understanding of the molecular mechanisms of cell death, cell cycle and proliferation and differentiation and the continuous improvement of gene introduction techniques, and with the increasing revelation of the regulatory network of auditory conduction pathways, gene therapy for deafness will no longer be limited to the exploration of a single approach, but will be a comprehensive treatment program integrating stem cell therapy, gene regulation and drug induction. Prevention of sensorineural deafness Newborn hearing screening is an important tool to achieve early detection and intervention of deafness. However, many deafnesses have been found to be of late onset and do not exhibit hearing loss at birth (including large vestibular aqueduct syndrome). Therefore, there are limitations to newborn hearing screening alone. Combining molecular screening with combined audiological and genetic screening in newborn hearing screening is an effective method to reduce the incidence [19], and in 2009, the Audiology Group of the Chinese Branch of Otolaryngology-Head and Neck Surgery and the Editorial Committee of the Chinese Journal of Otolaryngology-Head and Neck Surgery published the Guidelines for Early Hearing Detection and Intervention in Newborns and Infants (Draft) 》, marking that the diagnosis and intervention of hearing disorders in newborns in China are gradually becoming standardized [20]. Genetic diagnosis of deafness together with prenatal diagnosis is a key technology to ensure the re-birth of deaf families. Screening for common genetic mutations in deafness and routine clinical genetic diagnosis can identify a large number of families with hereditary deafness, and once these families identify their deaf children with double alleles of GJB2 and SLC26A4 mutations, their parents have a 25% risk of having another child, and prenatal diagnosis of the fetus can be performed by amniocentesis as early as 10 weeks of gestation when they become pregnant again, with a 75% chance that the fetus will carry only one or no There is a 75% chance that the fetus will carry only one or no mutated allele, which is not expected to duplicate the hearing structure of the prenatal carrier. In China, a significant percentage of sensorineural deafness is caused by the inappropriate use of aminoglycoside antibiotics such as streptomycin, gentamicin, kanamycin, and neomycin. It has been found that such patients are highly sensitive to these drugs due to mitochondrial gene mutations, thus causing “one shot deafness” in some patients. However, because of their low price, broad antibacterial spectrum, and good efficacy especially in the treatment of tuberculosis, aminoglycosides have not been completely withdrawn from the drug market. Mitochondrial gene testing prior to the use of such drugs can identify potential risks early and prevent deafness from occurring. The implementation of “one shot for deafness” prevention, deafness genetic diagnosis and prenatal diagnosis is a successful example of translational medicine. The laboratory “experimental” findings have been validated by clinical “trials” and have been applied to the clinical practice of diagnosis and prevention of hereditary deafness, avoiding the recurrence of deafness in individuals who do not carry the mitochondrial drug-deafness-sensitive mutation. This is an excellent model for translational medicine. Outlook Although molecular diagnosis of certain sensorineural hearing losses is now possible and can be used as a basis for prevention, the issue of treatment after diagnosis is still in its infancy. The future direction of development is still the interaction mechanism between genetic and environmental factors in the development of sensorineural hearing loss, the identification and function of new genes, biological treatment, hair cell regeneration, and the development of personalized and targeted therapeutic drugs. The implementation of the Ministry of Health’s policy of “moving the gate forward and prevention first”, the establishment of a hearing impairment prevention system in China, and the combination of hearing impairment prevention and genetic diagnosis technology in China are of historical significance to the development of the population quality project focusing on the prevention and early detection of birth defects in China. The effective prevention and low-cost treatment of sensorineural deafness is the ultimate goal to improve the quality of life of patients, and the research on the prevention and treatment of sensorineural deafness is of great significance.