Sensörinöral İşitme Kaybında Gen Terapi Yaklaşımları

Year 2022, Volume: 3 Issue: 1, 22 - 33, 30.01.2022

Kübra Kelleci

Abstract

İşitme kaybı, insanın sosyal ve bilişsel gelişimini ciddi şekilde
etkileyen dünya genelinde görülen en yaygın halk sağlık
problemlerinden biridir. İleri derece işitme kaybı ile karakterize
edilen sensörinöral işitme kaybı (SNİK), yetişkinlerde çok sık
görülmesine karşın tedavi yöntemleri harici işitme cihazı ve
koklear implant kullanımı ile sınırlıdır.
Moleküler genetik alanında meydana gelen gelişmeler, gen
düzenleme, gen susturma ve gen replasmanı gibi yöntemler
sayesinde özellikle iç kulak saç hücre rejenerasyonu
araştırmalarında büyük bir atılım yaparak, işitme ile ilgili
hastalıkların önlenmesinde ve tedavisinde yeni ve etkili bir
yol sağlamıştır. Bu çalışmada, genetik, ototoksisite, gürültü ve
yaşlılığa bağlı sensörinöral işitme kaybı yaşayan bireylerde,
işitme kaybını ortadan kaldırmak amacıyla araştırılan gen terapi
yaklaşımları derlenmiştir.

Keywords

Gen terapi, İç kulak, İşitme kaybı

References

• 1. Alberti, P. W. (2001). The anatomy and physiology of the ear and hearing. Occupational exposure to noise: Evaluation, prevention, and control, 53-62.
• 2. Ding, N., Lee, S., Lieber-Kotz, M., Yang, J., & Gao, X. (2021). Advances in genome editing for genetic hearing loss. Advanced drug delivery reviews, 168, 118-133.
• 3. Kujawa, S. G., & Liberman, M. C. (2009). Adding insult to injury: cochlear nerve degeneration after “temporary” noise-induced hearing loss. Journal of Neuroscience, 29(45), 14077-14085.
• 4. Kniss, J. S., Jiang, L., & Piotrowski, T. (2016). Insights into sensory hair cell regeneration from the zebrafish lateral line. Current opinion in genetics & development, 40, 32-40.
• 5. Anagnostopoulos, A.V. 2002. A compendium of Mouse knockouts with inner ear defects. Trends Genet. 18: S21– S38
• 6. Parkinson, N., and Brown, S.D. 2002. Focusing on the genetics of hearing: you ain’t heard nothin’ yet. Genome Biol. 3: comment2006.1–2006.6
• 7. Noben-Trauth, K. and Johnson, K.R. 2009. Inheritance patterns of progressive hearing loss in laboratory strains of mice. Brain Res. 1277: 42–51
• 8. Pennacchio, L. A. (2003). Insights from human/mouse genome comparisons. Mammalian genome, 14(7), 429-436.
• 9. Ingham, N. J., Pearson, S. A., Vancollie, V. E., Rook, V., Lewis, M. A., Chen, J., ... & Steel, K. P. (2019). Mouse screen reveals multiple new genes underlying mouse and human hearing loss. PLoS biology, 17(4), e3000194.
• 10. Yoshimura, H., Shibata, S. B., Ranum, P. T., Moteki, H., & Smith, R. J. (2019). Targeted allele suppression prevents progressive hearing loss in the mature murine model of human TMC1 deafness. Molecular Therapy, 27(3), 681-690.
• 11. Ohlemiller, K. K. (2006). Contributions of mouse models to understanding of ageand noise-related hearing loss. Brain research, 1091(1), 89-102.
• 12. Reis, A. D., Dalmolin, S. P., & Dallegrave, E. (2017). Animal models for hearing evaluations: a literature review. Revista Cefac, 19, 417-428.
• 13. Izumikawa, M., Minoda, R., Kawamoto, K., Abrashkin, K. A., Swiderski, D. L., Dolan, D. F., ... & Raphael, Y. (2005). Auditory hair cell replacement and hearing improvement by ATOH1 gene therapy in deaf mammals. Nature medicine, 11(3), 271-276.
• 14. DeSmidt, A. A., Zou, B., Grati, M. H., Yan, D., Mittal, R., Yao, Q., ... & Lu, Z. (2020). Zebrafish Model for Nonsyndromic X‐Linked Sensorineural Deafness, DFNX1. The Anatomical Record, 303(3), 544-555.
• 15. Zhang, W., Zhang, Y., Sood, R., Ranjan, S., Surovtseva, E., Ahmad, A., ... & Zou, J. (2011b). Visualization of intracellular trafficking of MATH1 protein in different cell types with a newly‐constructed nonviral gene delivery plasmid. The journal of gene medicine, 13(2), 134-144.
• 16. Schlecker, C., Praetorius, M., Brough, D. E., Presler, R. G., Hsu, C., Plinkert, P. K., & Staecker, H. (2011). Selective atonal gene delivery improves balance function in a mouse model of vestibular disease. Gene therapy, 18(9), 884-890.
• 17. Guan, M., Zhang, J., Jia, Y., Cao, X., Lou, X., Li, Y., & Gao, X. (2019). Middle ear structure and transcanal approach appropriate for middle ear surgery in rabbits. Experimental and therapeutic medicine, 17(2), 1248-1255.
• 18. György, B., Nist-Lund, C., Pan, B., Asai, Y., Karavitaki, K. D., Kleinstiver, B. P., ... & Corey, D. P. (2019). Allele-specific gene editing prevents deafness in a model of dominant progressive hearing loss. Nature medicine, 25(7), 1123-1130.
• 19. Ryu, N., Kim, M. A., Choi, D. G., Kim, Y. R., Sonn, J. K., Lee, K. Y., & Kim, U. K. (2019). CRISPR/Cas9-mediated genome editing of splicing mutation causing congenital hearing loss. Gene, 703, 83-90.
• 20. Han, M., Yu, D., Song, Q., Wang, J., Dong, P., & He, J. (2015). Polybrene: Observations on cochlear hair cell necrosis and minimal lentiviral transduction of cochlear hair cells. Neuroscience letters, 600, 164-170
• 21. Pietola, L., Aarnisalo, A. A., Joensuu, J., Pellinen, R., Wahlfors, J., & Jero, J. (2008). HOX-GFP and WOX-GFP lentivirus vectors for inner ear gene transfer. Acta oto-laryngologica, 128(6), 613-620.
• 22. Derby, M. L., Sena-Esteves, M., Breakefield, X. O., & Corey, D. P. (1999). Gene transfer into the mammalian inner ear using HSV-1 and vaccinia virus vectors. Hearing research, 134(1-2), 1-8.
• 23. Staecker, H., Liu, W., Malgrange, B., Lefebvre, P. P., & Van De Water, T. R. (2007). Vector-mediated delivery of bcl-2 prevents degeneration of auditory hair cells and neurons after injury. ORL, 69(1), 43-50.
• 24. Maguire, C. A., & Corey, D. P. (2020). Viral vectors for gene delivery to the inner ear. Hearing research, 394, 107927.
• 25. Tao, Y., Huang, M., Shu, Y., Ruprecht, A., Wang, H., Tang, Y., ... & Chen, Z. Y. (2018). Delivery of adeno-associated virus vectors in adult mammalian inner-ear cell subtypes without auditory dysfunction. Human gene therapy, 29(4), 492-506.
• 26. Gao, X., Tao, Y., Lamas, V., Huang, M., Yeh, W. H., Pan, B., et al. (2018). Treatment of autosomal dominant hearing loss by in vivo delivery of genome editing agents. Nature 553, 217–221. doi: 10.1038/nature25164.
• 27. Zhang, W., Zhang, Y., Löbler, M., Schmitz, K. P., Ahmad, A., Pyykkö, I., & Zou, J. (2011a). Nuclear entry of hyperbranched polylysine nanoparticles into cochlear cells. International journal of nanomedicine, 6, 535.
• 28. Belyantseva, I. A., Boger, E. T., Naz, S., Frolenkov, G. I., Sellers, J. R., Ahmed, Z. M., & Friedman, T. B. (2005). Myosin-XVa is required for tip localization of whirlin and differential elongation of hair-cell stereocilia. Nature cell biology, 7(2), 148-156.
• 29. Belyantseva, I. A., Boger, E. T., & Friedman, T. B. (2003). Myosin XVa localizes to the tips of inner ear sensory cell stereocilia and is essential for staircase formation of the hair bundle. Proceedings of the National Academy of Sciences, 100(24), 13958-13963.
• 30. Shu, Y., Tao, Y., Wang, Z., Tang, Y., Li, H., Dai, P., ... & Chen, Z. Y. (2016). Identification of adeno-associated viral vectors that target neonatal and adult mammalian inner ear cell subtypes. Human gene therapy, 27(9), 687-699.
• 31. Johnson, K. R., Tian, C., Gagnon, L. H., Jiang, H., Ding, D., & Salvi, R. (2017). Effects of Cdh23 single nucleotide substitutions on age-related hearing loss in C57BL/6 and 129S1/Sv mice and comparisons with congenic strains. Scientific reports, 7(1), 1-13.
• 32. Mianné, J., Chessum, L., Kumar, S., Aguilar, C., Codner, G., Hutchison, M., ... & Bowl, M. R. (2016). Correction of the auditory phenotype in C57BL/6N mice via CRISPR/Cas9-mediated homology directed repair. Genome medicine, 8(1), 1-12.
• 33. Belyantseva, I. A. (2009). Helios® Gene Gun–Mediated Transfection of the Inner Ear Sensory Epithelium. In Auditory and Vestibular Research (pp. 103-124). Humana Press.
• 34. Brigande, J. V., Gubbels, S. P., Woessner, D. W., Jungwirth, J. J., & Bresee, C. S. (2009). Electroporation-mediated gene transfer to the developing mouse inner ear. In Auditory and Vestibular Research (pp. 125-139). Humana Press.
• 35. Gubbels, S. P., Woessner, D. W., Mitchell, J. C., Ricci, A. J., & Brigande, J. V. (2008). Functional auditory hair cells produced in the mammalian cochlea by in utero gene transfer. Nature, 455(7212), 537-541.
• 36. Yeh, W. H., Chiang, H., Rees, H. A., Edge, A. S., & Liu, D. R. (2018). In vivo base editing of post-mitotic sensory cells. Nature communications, 9(1), 1-10.
• 37. Hastings, M. L., & Jones, T. A. (2019). Antisense oligonucleotides for the treatment of inner ear dysfunction. Neurotherapeutics, 16(2), 348-359.
• 38. Ahmed, H., Shubina-Oleinik, O., & Holt, J. R. (2017). Emerging gene therapies for genetic hearing loss. Journal of the Association for Research in Otolaryngology, 18(5), 649-670.
• 39. Yoshimura, H., Shibata, S. B., Ranum, P. T., & Smith, R. J. (2018). Enhanced viral-mediated cochlear gene delivery in adult mice by combining canal fenestration with round window membrane inoculation. Scientific reports, 8(1), 1-10.
• 40. Elbashir, S. M., Harborth, J., Lendeckel, W., Yalcin, A., Weber, K., & Tuschl, T. (2001). Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. nature, 411(6836), 494-498.
• 41. Karimian, A., Azizian, K., Parsian, H., Rafieian, S., Shafiei‐Irannejad, V., Kheyrollah, M., ... & Yousefi, B. (2019). CRISPR/Cas9 technology as a potent molecular tool for gene therapy. Journal of cellular physiology, 234(8), 12267-12277.
• 42. Hsu, P. D., Lander, E. S., & Zhang, F. (2014). Development and applications of CRISPR-Cas9 for genome engineering. Cell, 157(6), 1262-1278.
• 43. Cox, D. B. T., Platt, R. J., & Zhang, F. (2015). Therapeutic genome editing: prospects and challenges. Nature medicine, 21(2), 121-131.
• 44. Lustig, L., & Akil, O. (2019). Cochlear gene therapy. Cold Spring Harbor perspectives in medicine, 9(9), a033191.
• 45. Roberson, D. W., & Rubel, E. W. (1994). Cell division in the gerbil cochlea after acoustic trauma. American Journal of Otology, 15(1), 28-34.
• 46. Sobkowicz, H. M., August, B. K., & Slapnick, S. M. (1996). Post-traumatic survival and recovery of the auditory sensory cells in culture. Acta oto-laryngologica, 116(2), 257-262.
• 47. Cox, B. C., Chai, R., Lenoir, A., Liu, Z., Zhang, L., Nguyen, D. H., ... & Zuo, J. (2014). Spontaneous hair cell regeneration in the neonatal mouse cochlea in vivo. Development, 141(4), 816-829.
• 48. Golub, J. S., Tong, L., Ngyuen, T. B., Hume, C. R., Palmiter, R. D., Rubel, E. W., & Stone, J. S. (2012). Hair cell replacement in adult mouse utricles after targeted ablation of hair cells with diphtheria toxin. Journal of Neuroscience, 32(43), 15093-15105
• 49. Bucks, S. A., Cox, B. C., Vlosich, B. A., Manning, J. P., Nguyen, T. B., & Stone, J. S. (2017). Supporting cells remove and replace sensory receptor hair cells in a balance organ of adult mice. Elife, 6, e18128.
• 50. Fukui, H., & Raphael, Y. (2013). Gene therapy for the inner ear. Hearing research, 297, 99-105.
• 51. Bremer, H. G., Versnel, H., Hendriksen, F. G., Topsakal, V., Grolman, W., & Klis, S. F. (2014). Does vestibular end-organ function recover after gentamicin-induced trauma in Guinea pigs?. Audiology and Neurotology, 19(2), 135-150.
• 52. Bermingham, N. A., Hassan, B. A., Wang, V. Y., Fernandez, M., Banfi, S., Bellen, H. J., ... & Zoghbi, H. Y. (2001). Proprioceptor pathway development is dependent on MATH1. Neuron, 30(2), 411-422.
• 53. Akazawa, C., Ishibashi, M., Shimizu, C., Nakanishi, S., & Kageyama, R. (1995). A mammalian helix-loop-helix factor structurally related to the product of Drosophila proneural gene atonal is a positive transcriptional regulator expressed in the developing nervous system. Journal of Biological Chemistry, 270(15), 8730-8738.
• 54. Van Keymeulen, A., Mascre, G., Youseff, K. K., Harel, I., Michaux, C., De Geest, N., ... & Blanpain, C. (2009). Epidermal progenitors give rise to Merkel cells during embryonic development and adult homeostasis. Journal of cell biology, 187(1), 91-100
• 55. Yang, Q., Bermingham, N. A., Finegold, M. J., & Zoghbi, H. Y. (2001). Requirement of MATH1 for secretory cell lineage commitment in the mouse intestine. Science, 294(5549), 2155-2158.
• 56. Woods, C., Montcouquiol, M., & Kelley, M. W. (2004). MATH1 regulates development of the sensory epithelium in the mammalian cochlea. Nature neuroscience, 7(12), 1310-1318.
• 57. Cai, T., Jen, H. I., Kang, H., Klisch, T. J., Zoghbi, H. Y., & Groves, A. K. (2015). Characterization of the transcriptome of nascent hair cells and identification of direct targets of the ATOH1 transcription factor. Journal of Neuroscience, 35(14), 5870-5883.
• 58. Kawamoto, K., Ishimoto, S. I., Minoda, R., Brough, D. E., & Raphael, Y. (2003). MATH1 gene transfer generates new cochlear hair cells in mature guinea pigs in vivo. Journal of Neuroscience, 23(11), 4395-4400.
• 59. Walters, B. J., Coak, E., Dearman, J., Bailey, G., Yamashita, T., Kuo, B., & Zuo, J. (2017). In vivo interplay between p27Kip1, GATA3, ATOH1, and POU4F3 converts non-sensory cells to hair cells in adult mice. Cell reports, 19(2), 307-320.
• 60. Kelly, M. C., Chang, Q., Pan, A., Lin, X., & Chen, P. (2012). ATOH1 directs the formation of sensory mosaics and induces cell proliferation in the postnatal mammalian cochlea in vivo. Journal of Neuroscience, 32(19), 6699-6710.
• 61. Kuo, B. R., Baldwin, E. M., Layman, W. S., Taketo, M. M., & Zuo, J. (2015). In vivo cochlear hair cell generation and survival by coactivation of β-catenin and ATOH1. Journal of Neuroscience, 35(30), 10786-10798.
• 62. Maass, J. C., Berndt, F. A., Cánovas, J., & Kukuljan, M. (2013). p27Kip1 knockdown induces proliferation in the organ of Corti in culture after efficient shRNA lentiviral transduction. Journal of the Association for Research in Otolaryngology, 14(4), 495-508.
• 63. Cai, T., Seymour, M. L., Zhang, H., Pereira, F. A., & Groves, A. K. (2013). Conditional deletion of ATOH1 reveals distinct critical periods for survival and function of hair cells in the organ of Corti. Journal of Neuroscience, 33(24), 10110-10122.
• 64. Atkinson, P. J., Dong, Y., Gu, S., Liu, W., Najarro, E. H., Udagawa, T., & Cheng, A. G. (2018). Sox2 haploinsufficiency primes regeneration and Wnt responsiveness in the mouse cochlea. The Journal of clinical investigation, 128(4), 1641-1656
• 65. Bermingham, N. A., Hassan, B. A., Price, S. D., Vollrath, M. A., Ben-Arie, N., Eatock, R. A., ... & Zoghbi, H. Y. (1999). MATH1: an essential gene for the generation of inner ear hair cells. Science, 284(5421), 1837-1841.
• 66. Baker, K., Brough, D. E., & Sacken, H. (2009). Repair of the vestibular system via adenovector delivery of ATOH1: a potential treatment for balance disorders. Gene Therapy of Cochlear Deafness, 66, 52-63.
• 67. He, L., Guo, J. Y., Qu, T. F., Wei, W., Liu, K., Peng, Z., ... & Gong, S. S. (2020). Cellular origin and response of flat epithelium in the vestibular end organs of mice to ATOH1 overexpression. Hearing research, 391,107953.
• 68. Hicks, K. L., Wisner, S. R., Cox, B. C., & Stone, J. S. (2020). ATOH1 is required in supporting cells for regeneration of vestibular hair cells in adult mice. Hearing research, 385, 107838.
• 69. Zhang, W., Kim, S. M., Wang, W., Cai, C., Feng, Y., Kong, W., & Lin, X. (2018). Cochlear gene therapy for sensorineural hearing loss: current status and major remaining hurdles for translational success. Frontiers in molecular neuroscience, 11,221.
• 70. Hilgert, N., Smith, R. J., & Van Camp, G. (2009). Forty-six genes causing nonsyndromic hearing impairment: which ones should be analyzed in DNA diagnostics?. Mutation Research/Reviews in Mutation Research, 681(2-3), 189-196.
• 71. Iizuka, T., Kamiya, K., Gotoh, S., Sugitani, Y., Suzuki, M., Noda, T., ... & Ikeda, K. (2015). Perinatal Gjb2 gene transfer rescues hearing in a mouse model of hereditary deafness. Human molecular genetics, 24(13), 3651-3661.
• 72. Takada, Y., Beyer, L. A., Swiderski, D. L., O'Neal, A. L., Prieskorn, D. M., Shivatzki, S., ... & Raphael, Y. (2014). Connexin 26 null mice exhibit spiral ganglion degeneration that can be blocked by BDNF gene therapy. Hearing research, 309, 124-135.
• 73. Ryu, N., Kim, M. A., Park, D., Lee, B., Kim, Y. R., Kim, K. H., ... & Kim, U. K. (2018). Effective PEI-mediated delivery of CRISPR-Cas9 complex for targeted gene therapy. Nanomedicine: Nanotechnology, Biology and Medicine, 14(7), 2095-2102.
• 74. Kim, M. A., Kim, S. H., Ryu, N., Ma, J. H., Kim, Y. R., Jung, J., ... & Kim, U. K. (2019). Gene therapy for hereditary hearing loss by SLC26A4 mutations in mice reveals distinct functional roles of pendrin in normal hearing. Theranostics, 9(24), 7184.
• 75. Nist-Lund, C. A., Pan, B., Patterson, A., Asai, Y., Chen, T., Zhou, W., ... & Holt, J. R. (2019). Improved TMC1 gene therapy restores hearing and balance in mice with genetic inner ear disorders. Nature communications, 10(1), 1-14.
• 76. Shibata, S. B., Ranum, P. T., Moteki, H., Pan, B., Goodwin, A. T., Goodman, S. S., ... & Smith, R. J. (2016). RNA interference prevents autosomal-dominant hearing loss. The American Journal of Human Genetics, 98(6), 1101-1113.
• 77. Wu, P., Wu, X., Zhang, C., Chen, X., Huang, Y., & Li, H. (2021). Hair Cell Protection from Ototoxic Drugs. Neural Plasticity, 2021.
• 78. Kalyanam, B., Sarala, N., Mohiyuddin, S. A., & Diwakar, R. (2018). Auditory function and quality of life in patients receiving cisplatin chemotherapy in head and neck cancer: a case series follow-up study. Journal of cancer research and therapeutics, 14(5), 1099.
• 79. Li, H., & Steyger, P. S. (2011). Systemic aminoglycosides are trafficked via endolymph into cochlear hair cells. Scientific reports, 1(1), 1-5.
• 80. Marcotti, W., Van Netten, S. M., & Kros, C. J. (2005). The aminoglycoside antibiotic dihydrostreptomycin rapidly enters mouse outer hair cells through the mechano‐electrical transducer channels. The Journal of physiology, 567(2), 505-521
• 81. Ding, Y., Leng, J., Fan, F., Xia, B., & Xu, P. (2013). The role of mitochondrial DNA mutations in hearing loss. Biochemical genetics, 51(7), 588-602.
• 82. Langer, T., am Zehnhoff-Dinnesen, A., Radtke, S., Meitert, J., & Zolk, O. (2013). Understanding platinum-induced ototoxicity. Trends in pharmacological sciences, 34(8), 458-469.
• 83. Fetoni, A. R., Quaranta, N., Marchese, R., Cadoni, G., Paludetti, G., & Sergi, B. (2004). The protective role of tiopronin in cisplatin ototoxicity in Wistar rats. International journal of audiology, 43(8), 465-470.
• 84. Cai, J., Wu, X., Li, X., Ma, C., Xu, L., Guo, X., ... & Han, Y. (2019). Allicin protects against cisplatin-induced stria vascularis damage: Possible relation to inhibition of caspase-3 and PARP-1-AIF-mediated apoptotic pathways. ORL, 81(4), 202-214.
• 85. Zhang, Y., Li, W., He, Z., Wang, Y., Shao, B., Cheng, C., ... & Gao, X. (2019). Pre-treatment with fasudil prevents neomycin-induced hair cell damage by reducing the accumulation of reactive oxygen species. Frontiers in Molecular Neuroscience, 12, 264.
• 86. Yu, X., Liu, W., Fan, Z., Qian, F., Zhang, D., Han, Y., ... & Wang, H. (2017). c-Myb knockdown increases the neomycin-induced damage to hair-cell-like HEI-OC1 cells in vitro. Scientific Reports, 7(1), 1-14.
• 87. Garcia‐Berrocal, J. R., Nevado, J., Ramirez‐Camacho, R., Sanz, R., González‐García, J. A., Sánchez‐Rodríguez, C., ... & Trinidad Cabezas, A. (2007). The anticancer drug cisplatin induces an intrinsic apoptotic pathway inside the inner ear. British journal of pharmacology, 152(7), 1012-1020.
• 88. Gentilin, E., Simoni, E., Candito, M., Cazzador, D., & Astolfi, L. (2019). Cisplatin-induced ototoxicity: updates on molecular targets. Trends in molecular medicine, 25(12), 1123-1132.
• 89. Zheng, J. L., & Gao, W. Q. (2000). Overexpression of MATH1 induces robust production of extra hair cells in postnatal rat inner ears. Nature neuroscience, 3(6),580-586.
• 90. Kraft, S., Hsu, C., Brough, D. E., & Staecker, H. (2013). ATOH1 induces auditory hair cell recovery in mice after ototoxic injury. The Laryngoscope, 123(4), 992-999.
• 91. Fetoni, A. R., Eramo, S. L. M., Rolesi, R., Troiani, D., & Paludetti, G. (2012). Antioxidant treatment with coenzyme Q-ter in prevention of gentamycin ototoxicity in an animal model. Acta Otorhinolaryngologica Italica, 32(2), 103.
• 92. Campbell, K. C., Martin, S. M., Meech, R. P., Hargrove, T. L., Verhulst, S. J., & Fox, D. J. (2016). D-methionine (D-met) significantly reduces kanamycin-induced ototoxicity in pigmented guinea pigs. International journal of audiology, 55(5), 273- 278.
• 93. Ekborn, A., Laurell, G., Ehrsson, H., & Miller, J. (2003). Intracochlear administration of thiourea protects against cisplatin-induced outer hair cell loss in the guinea pig. Hearing research, 181(1-2), 109-115.
• 94. Yang, S. M., Chen, W., Guo, W. W., Jia, S., Sun, J. H., Liu, H. Z., ... & He, D. Z. (2012). Regeneration of stereocilia of hair cells by forced ATOH1 expression in the adult mammalian cochlea.
• 95. Clifford, R. E., Hoffer, M., & Rogers, R. (2016). The genomic basis of noise-induced hearing loss: A literature review organized by cellular pathways. Otology & Neurotology, 37(8), e309-e316.
• 96. Cunningham, L. L., & Tucci, D. L. (2017). Hearing loss in adults. New England Journal of Medicine, 377(25), 2465-2473.
• 97. Huang, Q., & Tang, J. (2010). Age-related hearing loss or presbycusis. European Archives of Oto-rhino-laryngology, 267(8), 1179-1191.
• 98. Gates, G. A., Couropmitree, N. N., & Myers, R. H. (1999). Genetic associations in age-related hearing thresholds. Archives of otolaryngology–head & neck surgery, 125(6), 654-659.
• 99. Bared, A., Ouyang, X., Angeli, S., Du, L. L., Hoang, K., Yan, D., & Liu, X. Z. (2010). Antioxidant enzymes, presbycusis, and ethnic variability. Otolaryngology—Head and Neck Surgery, 143(2), 263-268.
• 100. Van Laer, L., Van Eyken, E., Fransen, E., Huyghe, J. R., Topsakal, V., Hendrickx, J. J., ... & Van Camp, G. (2008). The grainyhead like 2 gene (GRHL2), alias TFCP2L3, is associated with age-related hearing impairment. Human molecular genetics, 17(2), 159-169.
• 101. Arnett, J., Emery, S. B., Kim, T. B., Boerst, A. K., Lee, K., Leal, S. M., & Lesperance, M. M. (2011). Autosomal dominant progressive sensorineural hearing loss due to a novel mutation in the KCNQ4 gene. Archives of Otolaryngology–Head & Neck Surgery, 137(1), 54-59.
• 102. 102.Uchida, Y., Sugiura, S., Nakashima, T., Ando, F., & Shimokata, H. (2009). Endothelin‐1 gene polymorphism and hearing impairment in elderly Japanese. The Laryngoscope, 119(5), 938-943.
• 103. Sugiura, S., Uchida, Y., Nakashima, T., Ando, F., & Shimokata, H. (2010). The association between gene polymorphisms in uncoupling proteins and hearing impairment in Japanese elderly. Acta oto-laryngologica, 130(4), 487-492.
• 104. Newman, D. L., Fisher, L. M., Ohmen, J., Parody, R., Fong, C. T., Frisina, S. T., ... & Friedman, R. A. (2012). GRM7 variants associated with age-related hearing loss based on auditory perception. Hearing research, 294(1-2), 125-132.
• 105. Friedman, R. A., Van Laer, L., Huentelman, M. J., Sheth, S. S., Van Eyken, E., Corneveaux, J. J., ... & Van Camp, G. (2009). GRM7 variants confer susceptibility to age-related hearing impairment. Human molecular genetics, 18(4), 785-796.
• 106. Van Laer, L., Huyghe, J. R., Hannula, S., Van Eyken, E., Stephan, D. A., Mäki-Torkko, E., ... & Van Camp, G. (2010). A genome-wide association study for age-related hearing impairment in the Saami. European Journal of Human Genetics, 18(6), 685-693.
• 107. Van Eyken, E., Van Camp, G., Fransen, E., Topsakal, V., Hendrickx, J. J., Demeester, K., ... & Van Laer, L. (2007). Contribution of the N-acetyltransferase 2 polymorphism NAT2* 6A to age-related hearing impairment. Journal of medical genetics, 44(9), 570-578.
• 108. Ünal, M., Tamer, L., Doğruer, Z. N., Yildirim, H., Vayisoğlu, Y., & Çamdeviren, H. (2005). N‐acetyltransferase 2 gene polymorphism and presbycusis. The Laryngoscope, 115(12), 2238-2241.
• 109. Noben-Trauth, K., Zheng, Q. Y., & Johnson, K. R. (2003). Association of cadherin 23 with polygenic inheritance and genetic modification of sensorineural hearing loss. Nature genetics, 35(1), 21-23.
• 110. Charizopoulou, N., Lelli, A., Schraders, M., Ray, K., Hildebrand, M. S., Ramesh, A., ... & Noben-Trauth, K. (2011). Gipc3 mutations associated with audiogenic seizures and sensorineural hearing loss in mouse and human. Nature communications, 2(1), 1-12.
• 111. Pang, J., Xiong, H., Ou, Y., Yang, H., Xu, Y., Chen, S., ... & Zheng, Y. (2019). SIRT1 protects cochlear hair cell and delays age-related hearing loss via autophagy. Neurobiology of aging, 80, 127-137.
• 112. Liu Y, Chu H, Chen J, Zhou L, Chen Q, Yu Y, et al. Agerelated change in the expression of NKCC1 in the cochlear lateral wall of C57BL/6J mice. Acta Otolaryngol. 2014;134(10):1047-51.
• 113. Dong, Y., Li, M., Liu, P., Song, H., Zhao, Y., & Shi, J. (2014). Genes involved in immunity and apoptosis are associated with human presbycusis based on microarray analysis. Acta oto-laryngologica, 134(6), 601-608.
• 114. Wiwatpanit, T., Remis, N. N., Ahmad, A., Zhou, Y., Clancy, J. C., Cheatham, M. A., & García-Añoveros, J. (2018). Codeficiency of lysosomal mucolipins 3 and 1 in cochlear hair cells diminishes outer hair cell longevity and accelerates age-related hearing loss. Journal of Neuroscience, 38(13), 3177-3189.
• 115. Kytövuori, L., Hannula, S., Mäki-Torkko, E., Sorri, M., & Majamaa, K. (2017). A nonsynonymous mutation in the WFS1 gene in a Finnish family with age-related hearing impairment. Hearing research, 355, 97-101.
• 116. Lin, X., Li, G., Zhang, Y., Zhao, J., Lu, J., Gao, Y., ... & Wu, H. (2019). Hearing consequences in Gjb2 knock-in mice: implications for human p. V37I mutation. Aging (Albany NY), 11(18), 7416.
• 117. Salehi, P., Ge, M. X., Gundimeda, U., Michelle Baum, L., Lael Cantu, H., Lavinsky, J., ... & Friedman, R. A. (2017). Role of Neuropilin-1/Semaphorin-3A signaling in the functional and morphological integrity of the cochlea. PLoS genetics, 13(10), e1007048.
• 118. 118.Bouzid, A., Smeti, I., Dhouib, L., Roche, M., Achour, I., Khalfallah, A., ... & Masmoudi, S. (2018). Down-expression of P2RX2, KCNQ5, ERBB3 and SOCS3 through DNA hypermethylation in elderly women with presbycusis. Biomarkers, 23(4), 347-356.
• 119. 119.Falah, M., Najafi, M., Houshmand, M., & Farhadi, M. (2016). Expression levels of the BAK1 and BCL2 genes highlight the role of apoptosis in age-related hearing impairment. Clinical interventions in aging, 11, 1003
• 120. Taylor, R. R., Filia, A., Paredes, U., Asai, Y., Holt, J. R., Lovett, M., & Forge, A. (2018). Regenerating hair cells in vestibular sensory epithelia from humans. Elife, 7, e34817.
• 121. Wang, T., Chai, R., Kim, G. S., Pham, N., Jansson, L., Nguyen, D. H., ... & Cheng, A. G. (2015). Lgr5+ cells regenerate hair cells via proliferation and direct transdifferentiation in damaged neonatal mouse utricle. Nature communications, 6(1), 1-15.
• 122. Wu, J., Li, W., Lin, C., Chen, Y., Cheng, C., Sun, S., ... & Li, H. (2016). Co-regulation of the Notch and Wnt signaling pathways promotes supporting cell proliferation and hair cell regeneration in mouse utricles. Scientific reports, 6(1), 1-16.
• 123. Ginn, S. L., Amaya, A. K., Alexander, I. E., Edelstein, M., & Abedi, M. R. (2018). Gene therapy clinical trials worldwide to 2017: An update. The journal of gene medicine, 20(5), e3015.
• 124. Chen, H., Xing, Y., Xia, L., Chen, Z., Yin, S., & Wang, J. (2018). AAV-mediated NT-3 overexpression protects cochleae against noise-induced synaptopathy. Gene therapy, 25(4), 251-259.
• 125. Kikkawa, Y., Seki, Y., Okumura, K., Ohshiba, Y., Miyasaka, Y., Suzuki, S., ... & Yonekawa, H. (2012). Advantages of a mouse model for human hearing impairment. Experimental animals, 61(2), 85-98.