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Gentherapie und Stammzellen für das Innenohr

Ein Überblick

Gene therapy and stem cells for the inner ear

A review

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Zusammenfassung

Das Innenohr ist in der Hals-Nasen-Ohren-Heilkunde wohl das wichtigste Ziel, bei dem die Gen- und Stammzelltherapie zukünftig ein Teil innovativer Behandlungsstrategien werden können. Die Schallempfindungsschwerhörigkeit ist, war und wird eine große therapeutische Herausforderung sein. Das gegenwärtige Management ist nicht kausal orientiert. Seit den ersten Versuchen 1994 durch Fujiyoshi, eine genbasierte, spezifisch auf das Innenohr abzielende Therapie zu entwickeln, sind einige weitere Erkenntnisse gesammelt worden. Im Labor wurden Fortschritte im Bereich der Genetik, des Verständnisses molekularer Signalwege, der Haarzellentwicklung und -regeneration und der Stammzellbiologie erzielt. Dadurch wurde auch die mögliche Rolle dieser zellulären und intrazellulären Werkzeuge für eine anwendbare Lösung zur Behandlung von Innenohrerkrankungen in der Zukunft erkennbar. Hier wird ein Überblick über den aktuellen Stand in den wesentlichen Forschungszweigen gegeben.

Abstract

Within the field of otolaryngology, the inner ear is perhaps the most important target for which stem cell and gene therapy may comprise elements of primary intervention strategies in the future. As it has done in the past, sensorineural hearing loss still represents a major therapeutic challenge—and it will continue to do so in the future. Current management strategies are not cause-orientated. Since the first experiments aimed at developing a middle ear-specific gene-based therapy by Fujiyoshi in 1994, several new discoveries have been made. In the laboratory, advances in the fields of genetics, molecular signalling, stem cell biology and hair cell development and regeneration have been made. Through these advances, the potential roll of cellular and intracellular tools for the future treatment of hearing loss has been recognized. This paper comprises a review of the current status of important areas of research.

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Literatur

  1. Ahmad S, Tang W, Chang Q et al (2007) Restoration of connexin26 protein level in the cochlea completely rescues hearing in a mouse model of human connexin30-linked deafness. Proc Natl Acad Sci U S A 104:1337–1341

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  2. Akil O, Seal R, Burke K et al (2012) Restoration of hearing in the VGLUT3 knockout mouse using virally mediated gene therapy. Neuron 75:283–293

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Albu S, Muresanu D (2012) Vestibular regeneration – experimental models and clinical implications. J Cell Mol Med 16:1970–1977

    Article  PubMed  Google Scholar 

  4. Ambros V (2004) The functions of animal microRNAs. Nature 431:350–355

    Article  CAS  PubMed  Google Scholar 

  5. Bedrosian J, Gratton M, Brigande J et al (2006) In vivo delivery of recombinant viruses to the fetal murine cochlea: trans-duction characteristics and long-term effects on auditory function. Mol Ther 14:328–335

    Article  CAS  PubMed  Google Scholar 

  6. Bermingham N, Hassan B, Price S et al (1999) Math1: an essential gene for generation of inner ear hair cells. Science 284

  7. Buckiova D, Ranjan S, Newman T et al (2012) Minimally invasive drug delivery to the cochlea through application of nanoparticles to the round window membrane. Nanomedicine (Lond) 7:1339–1354

    Google Scholar 

  8. Cooper L, Chan D, Roediger F et al (2006) AAV-mediated delivery of the caspase inhibitor XIAP protects against cisplatin ototoxicity. Otol Neurotol 27:484–490

    Article  PubMed  Google Scholar 

  9. Cox B, Luiu Z, Lagarde M et al (2012) Conditional gene expression in the mouse inner ear using Cre-loxP. J Assoc Res Otolaryngol 13:295–322

    Article  PubMed Central  PubMed  Google Scholar 

  10. Chaikhoutdinov I, Goldenberg D (2013) Impact of genetic targets on therapy in head and neck squamous cell carcinoma. Adv Exp Med Biol 779:165–177

    Article  PubMed  Google Scholar 

  11. Dorsey K, Agulnik M (2013) Promising new molecular targeted therapies in head and neck cancer. Drugs 73:315–325

    Article  CAS  PubMed  Google Scholar 

  12. Fire A, Xu S, Montogomery M et al (1998) Potent and specific genetic interference by double stranded RNA in Caenorhabditis elegans. Nature 391:806–811

    Article  CAS  PubMed  Google Scholar 

  13. Forge A, Li L, Corwin J et al (1993) Ultrastructureal evidence for hair cell regeneration in the mammalian inner ear. Science 259:1616–1619

    Article  CAS  PubMed  Google Scholar 

  14. Fritzsch B, Pauley S, Beisel K (2006) Cells molecules and morphogenesis: the making of the vertebrate ear. Brain Res 1091:151–171

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Fritzsch B, Tessarollo L, Coppola E et al (2004) Neurotrophins in the ear: their roles in sensory neuron survival and fiber guidence. Prog Brain Res 146

  16. Fujiyoshi T, Hood L, Yoo T (1994) Restoration of brain stem auditory-evoked potentials by gene transfer in shiverer mice. Ann Otol Rhinol Laryngol 103:449–456

    CAS  PubMed  Google Scholar 

  17. Fukui H, Raphael Y (2013) Gene therapy for the inner ear. Hear Res 297:99–105

    Article  CAS  PubMed  Google Scholar 

  18. Fukui H, Wong H, Beyer L et al (2012) BDNF gene therapy induces auditory nerve survival and fiber sprouting in deaf Pou4f3 mutant mice. Sci Rep 2:838

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Gaylor J, Raman G, Chung M et al (2013) Cochlear implantation in adults: a systematic review and meta-analysis. JAMA Otolaryngol Head Neck Surg 139:262–272

    Article  Google Scholar 

  20. Gifford R, Dorman M, Skarzynski H et al (2013) Cochlear implantation with hearing preservation yields significant benefit for speech recognition in complex listening environments. Ear Hear 34:413–425

    Article  PubMed  Google Scholar 

  21. Giraldez F, Fritzsch B (2007) The molecular biology of ear development – „twenty years are nothing“. Int J Dev Biol 51:429–438

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Glueckert R, Bitsche M, Miller M et al (2008) Deafferentattion-associated changes in afferent and efferent processes in the guinea pig cochlea and afferent regeneration with chronic intrascalar brain-derived neurotrophic factor and acidic fibroblast growth factor. J Comp Neurol 507:1602–1621

    Article  PubMed  Google Scholar 

  23. Griesenbach U, Alton E (2013) Moving forward: cystic fibrosis gene therapy. Hum Mol Genet 22:R51–R58

    Article  Google Scholar 

  24. Han Z, Yang J, Chi F et al (2010) Survival and fate of transplanted embryonic neural stem cells by Atoh1 gene transfer in guinea pigs cochlea. Neuroreport 21:490–496

    Article  CAS  PubMed  Google Scholar 

  25. Hawkins R, Bashiardes S, Helms C et al (2003) Gene expression differences in quiescent versus regenerating hair cells of avian sensory epithelia: implications for human hearing and balance disorders. Hum Mol Genet 12:1261–1272

    Article  CAS  PubMed  Google Scholar 

  26. Hawkins R, Bashiardes S, Powder K et al (2007) Large scale gene expression profiles of regenerating inner ear sensory epithelia. PLoS One 2:e525

    Article  PubMed Central  PubMed  Google Scholar 

  27. Hoffman T (2012) Systemic therapy strategies for head-neck carcinomas: current status. Laryngorhinootologie 91:S123–S143

    Google Scholar 

  28. Husseman J, Raphael Y (2009) Gene therapy in the inner ear using adenovirus vectors. Adv Otorhinolaryngol 66:37–51

    CAS  PubMed  Google Scholar 

  29. Ito J, Kojima K, Kawaguchi S (2001) Survival of neural stem in the cochlea. Acta Otolaryngol 121:140–142

    Article  CAS  PubMed  Google Scholar 

  30. Kawamoto K, Yagi M, Stover T et al (2003) Hearing and hair cells are protected by adenoviral gene therapy with TGF-beta1 and GDNF. Mol Ther 7:484–492

    Article  CAS  PubMed  Google Scholar 

  31. Li H, Liu H, Heller S (2003) Pluripotent stem cells from the adult mouse inner ear. Nat Med 9:1293–1299

    Article  CAS  PubMed  Google Scholar 

  32. Maass J, Carrasco L, Dentone L et al (2009) Genetic therapy as molecular tool for hair cell regeneration. Rev Otorrinolaringol Cir Cabeza Cuello 69:55–60

    Article  Google Scholar 

  33. Maeda Y, Fukushima K, Nishizaki K et al (2005) In vitro and in vivo suppression of GJB2 expression by RNA interference. Hum Mol Genet 14:1641–1650

    Article  CAS  PubMed  Google Scholar 

  34. Majoros I, Williams C, Tomalia D et al (2008) New dendrimers: syntesis and characterization of popam – pamam hybrid dendrimers. Macromolecules 41:8372–8379

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Matsumoto M, Nakagawa T, Kojima K et al (2008) Potential of embryonic stem cell-derived neurons for synapse formation with auditory hair cells. J Neurosci Res 86:3075–3085

    Article  CAS  PubMed  Google Scholar 

  36. Nanoci (2013) Nanotechnology based cochlear implants. [Online im Internet:]. http://www.nanoci.org [Stand: 14.10.2013; 18:11 Uhr]

  37. National Institute of Health N (1995) Cochlear implants in adults and children. NIH Consens Statement 13:1–30

    Google Scholar 

  38. Okano T, Kelley M (2012) Stem cell therapy for the inner ear: recent advances and future directions. Trends Amplif 16:4–18

    Article  PubMed  Google Scholar 

  39. Oshima K, Shin K, Diensthuber M et al (2010) Mechanosensitive hair cell-like cells from embryonic and induced pluripotent stem cells. Cell 141:704–716

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. Pfannenstiel S, Praetorius M (2008) Protektion und Regeneration sensorischer Epithelien des Innenohres. HNO 56:13–20

    Article  CAS  PubMed  Google Scholar 

  41. Platt M, Metson R, Stankovic K (2009) Gene-expression signatures of nasal polyps associated with chronic rhinosinusitis and aspirin-sensitive asthma. Curr Opin Allergy Clin Inmunol 9:23–28

    Article  CAS  Google Scholar 

  42. Praetorius M, Staecker H, Plinkert P (2009) Chirurgische Techik der Kochleaimplantation. HNO 57:663–670

    Article  CAS  PubMed  Google Scholar 

  43. Ronaghi M, Nasr M, Heller S (2012) Concise review: inner ear stem cells – an oxymoron, but why? Stem Cells 30:69–74

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  44. Rubel E, Dew L, Roberson D (1995) Mammalian vestibular hair cell regeneration. Science 267:701–707

    Article  CAS  PubMed  Google Scholar 

  45. Rubel E, Fritzsch B (2002) Auditory system development: primary auditory neurons and their targets. Annu Rev Neurosci 25:51–101

    Article  CAS  PubMed  Google Scholar 

  46. Rubel E, Furrerm S, Stone J (2013) A brief history of hair cell regeneration research and speculations on the future. Hear Res 297:42–51

    Article  PubMed  Google Scholar 

  47. Schlecker C, Praetorius M, Brough D et al (2011) Selective atonal gene delivery improves balance function in a mouse model of vestibular disease. Gene Ther 18:884–890

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  48. Shi F, Edge A (2013) Prospects for replacement of auditory neurons by stem cells. Hear Res 297:106–112

    Article  CAS  PubMed  Google Scholar 

  49. Shibita S, Cortez S, Wiler J et al (2012) Hyaluronic acid enhances gene delivery into the cochlea. Hum Gene Ther 23:302–310

    Article  Google Scholar 

  50. Staecker H, Praetorius M, Brough D (2011) Development of gene therapy for inner ear disease: using bilateral vestibular hypofunction as a vehicle for translational research. Hear Res 276:44–51

    Article  PubMed Central  PubMed  Google Scholar 

  51. Sun H, Huan A, Cao S (2011) Current status and prospects of gene therapy for the inner ear. Hum Gene Ther 22:1311–1322

    Article  CAS  PubMed  Google Scholar 

  52. Tamura T, Kita T, Nakagawa T et al (2005) Drug delivery to the cochlea using PLGA nanoparticles. Laryngoscope 115:2000–2005

    Article  CAS  PubMed  Google Scholar 

  53. Thomas S, Grandis J (2009) The current state of head and neck cancer gene therapy. Hum Gene Ther 20:1565–1575

    Article  CAS  PubMed  Google Scholar 

  54. Vickers T, Koo S, Bennet C et al (2003) Efficient reduction of target RNAs by small interfering RNA and RNase H-dependent antisense agents. A comparative analysis. J Biol Chem 278:7108–7118

    Article  CAS  PubMed  Google Scholar 

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Einhaltung ethischer Richtlinien

Interessenkonflikt. H.A. Breinbauer und M. Praetorius geben an, dass kein Interessenkonflikt besteht. Dieser Beitrag beinhaltet keine Studien an Menschen oder Tieren.

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  1. Sektion Otologie und Neurootologie, Hals-Nasen-Ohren-Klinik, Universitätsklinikum Heidelberg, Im Neuenheimer Feld 400, 69120, Heidelberg, Deutschland

    H.A. Breinbauer & M. Praetorius

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  1. H.A. Breinbauer
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  2. M. Praetorius
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Correspondence to H.A. Breinbauer.

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Breinbauer, H., Praetorius, M. Gentherapie und Stammzellen für das Innenohr. HNO 62, 93–99 (2014). https://doi.org/10.1007/s00106-013-2822-0

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