Download PDF
Semin Hear 2006; 27(3): 193-204
DOI: 10.1055/s-2006-947286
Copyright © 2006 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Future Trends and Potential for Treatment of Sensorineural Hearing Loss

Zippora Brownstein1 , Karen B. Avraham1
  • 1Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
Further Information

Publication History

Publication Date:
17 July 2006 (online)

    Permissions and Reprints

ABSTRACT

Damage and loss of hair cells in the inner ear is the most frequent cause of hearing loss (HL), since mammalian hair cells are not replenished once lost. To date, the treatment of HL consists of hearing aids or cochlear implants, but both options restore hearing with limited success. Gene therapy is an attractive option as a means for treating sensorineural hearing impairment, although at present it is investigational. The finding that hair cells can regenerate in nonmammalian vertebrates has triggered many studies, with the hope of simulating a similar process in humans. Current research that focuses on the auditory pathways, the genes involved in HL, efficient ways to transfer therapeutic agents into the inner ear, and optimization of gene manipulation, gene therapy, and stem cell treatment raises hope for restoring hearing and curing deafness.

KEYWORDS

Deafness - cochlea - gene therapy - vectors - regeneration - stem cells

REFERENCES

  • 1 Estivill X, Fortina P, Surrey S et al.. Connexin-26 mutations in sporadic and inherited sensorineural deafness.  Lancet. 1998;  351 394-398
    CrossrefPubMedGoogle Scholar
  • 2 Nadol Jr J B. Hearing loss.  N Engl J Med. 1993;  329 1092-1102
    CrossrefPubMedGoogle Scholar
  • 3 Zlotogora J, Barges S. High incidence of profound deafness in an isolated community.  Genet Test. 2003;  7 143-145
    CrossrefPubMedGoogle Scholar
  • 4 Denoyelle F, Marlin S, Weil D et al.. Clinical features of the prevalent form of childhood deafness, DFNB1, due to a connexin-26 gene defect: implications for genetic counselling.  Lancet. 1999;  353 1298-1303
    CrossrefPubMedGoogle Scholar
  • 5 Forge A, Becker D, Casalotti S, Edwards J, Marziano N, Nevill G. Gap junctions in the inner ear: comparison of distribution patterns in different vertebrates and assessment of connexin composition in mammals.  J Comp Neurol. 2003;  467 207-231
    CrossrefPubMedGoogle Scholar
  • 6 Linthicum Jr F H, Anderson W. Cochlear implantation of totally deaf ears. Histologic evaluation of candidacy.  Acta Otolaryngol. 1991;  111 327-331
    PubMedGoogle Scholar
  • 7 Chen A H, Mueller R F, Prasad S D et al.. Presymptomatic diagnosis of nonsyndromic hearing loss by genotyping.  Arch Otolaryngol Head Neck Surg. 1998;  124 20-24
    PubMedGoogle Scholar
  • 8 Nadol Jr J B. Patterns of neural degeneration in the human cochlea and auditory nerve: implications for cochlear implantation.  Otolaryngol Head Neck Surg. 1997;  117 220-228
    CrossrefPubMedGoogle Scholar
  • 9 Berlin C I, Hood L, Morlet T, Rose K, Brashears S. Auditory neuropathy/dys-synchrony: diagnosis and management.  Ment Retard Dev Disabil Res Rev. 2003;  9 225-231
    CrossrefPubMedGoogle Scholar
  • 10 Cotanche D A. Regeneration of hair cell stereociliary bundles in the chick cochlea following severe acoustic trauma.  Hear Res. 1987;  30 181-195
    CrossrefPubMedGoogle Scholar
  • 11 Cruz R M, Lambert P R, Rubel E W. Light microscopic evidence of hair cell regeneration after gentamicin toxicity in chick cochlea.  Arch Otolaryngol Head Neck Surg. 1987;  113 1058-1062
    PubMedGoogle Scholar
  • 12 Weisleder P, Rubel E W. Hair cell regeneration after streptomycin toxicity in the avian vestibular epithelium.  J Comp Neurol. 1993;  331 97-110
    PubMedGoogle Scholar
  • 13 Bianchi L M, Raz Y. Methods for providing therapeutic agents to treat damaged spiral ganglion neurons.  Curr Drug Targets CNS Neurol Disord. 2004;  3 195-199
    CrossrefPubMedGoogle Scholar
  • 14 Ishimoto S, Kawamoto K, Kanzaki S, Raphael Y. Gene transfer into supporting cells of the organ of Corti.  Hear Res. 2002;  173 187-197
    CrossrefPubMedGoogle Scholar
  • 15 Duan M, Venail F, Spencer N, Mezzina M. Treatment of peripheral sensorineural hearing loss: gene therapy.  Gene Ther. 2004;  11(suppl 1) S51-S56
    CrossrefPubMedGoogle Scholar
  • 16 Kessel R G, Kardon R H. The shape, polarization, and innervation of sensory hair cells in the guinea pig crista ampullaris and macula utriculi.  Scan Electron Microsc. 1979;  967-974, 962
    PubMedGoogle Scholar
  • 17 Schuknecht H F. Pathology of the Ear. Philadelphia, PA; Lea & Febiger 1993
    Google Scholar
  • 18 Chen Z, Ulfendahl M, Ruan R, Tan L, Duan M. Protection of auditory function against noise trauma with local caroverine administration in guinea pigs.  Hear Res. 2004;  197 131-136
    CrossrefPubMedGoogle Scholar
  • 19 Jero J, Mhatre A N, Tseng C J et al.. Cochlear gene delivery through an intact round window membrane in mouse.  Hum Gene Ther. 2001;  12 539-548
    CrossrefPubMedGoogle Scholar
  • 20 Lalwani A K, Jero J, Mhatre A N. Current issues in cochlear gene transfer.  Audiol Neurootol. 2002;  7 146-151
    CrossrefPubMedGoogle Scholar
  • 21 Ernfors P, Duan M L, ElShamy W M, Canlon B. Protection of auditory neurons from aminoglycoside toxicity by neurotrophin-3.  Nat Med. 1996;  2 463-467
    CrossrefPubMedGoogle Scholar
  • 22 Duan M, Agerman K, Ernfors P, Canlon B. Complementary roles of neurotrophin 3 and a N-methyl-D-aspartate antagonist in the protection of noise and aminoglycoside-induced ototoxicity.  Proc Natl Acad Sci USA. 2000;  97 7597-7602
    CrossrefPubMedGoogle Scholar
  • 23 Hoffer M E, Balough B J, Gottshall K R et al.. Sustained-release devices in inner ear medical therapy.  Otolaryngol Clin North Am. 2004;  37 1053-1060
    CrossrefPubMedGoogle Scholar
  • 24 Lalwani A K, Mhatre A N. Cochlear gene therapy.  Ear Hear. 2003;  24 342-348
    PubMedGoogle Scholar
  • 25 Maiorana C R, Staecker H. Advances in inner ear gene therapy: exploring cochlear protection and regeneration.  Curr Opin Otolaryngol Head Neck Surg. 2005;  13 308-312
    PubMedGoogle Scholar
  • 26 Balak K J, Corwin J T, Jones J E. Regenerated hair cells can originate from supporting cell progeny: evidence from phototoxicity and laser ablation experiments in the lateral line system.  J Neurosci. 1990;  10 2502-2512
    PubMedGoogle Scholar
  • 27 Cotanche D A. Structural recovery from sound and aminoglycoside damage in the avian cochlea.  Audiol Neurootol. 1999;  4 271-285
    CrossrefPubMedGoogle Scholar
  • 28 Stone J S, Oesterle E C, Rubel E W. Recent insights into regeneration of auditory and vestibular hair cells.  Curr Opin Neurol. 1998;  11 17-24
    PubMedGoogle Scholar
  • 29 Forge A, Li L, Corwin J T, Nevill G. Ultrastructural evidence for hair cell regeneration in the mammalian inner ear.  Science. 1993;  259 1616-1619
    PubMedGoogle Scholar
  • 30 Lopez I, Honrubia V, Lee S C, Schoeman G, Beykirch K. Quantification of the process of hair cell loss and recovery in the chinchilla crista ampullaris after gentamicin treatment.  Int J Dev Neurosci. 1997;  15 447-461
    PubMedGoogle Scholar
  • 31 Bermingham-McDonogh O, Rubel E W. Hair cell regeneration: winging our way towards a sound future.  Curr Opin Neurobiol. 2003;  13 119-126
    CrossrefPubMedGoogle Scholar
  • 32 Matsui J I, Cotanche D A. Sensory hair cell death and regeneration: two halves of the same equation.  Curr Opin Otolaryngol Head Neck Surg. 2004;  12 418-425
    PubMedGoogle Scholar
  • 33 Torres M, Giraldez F. The development of the vertebrate inner ear.  Mech Dev. 1998;  71 5-21
    CrossrefPubMedGoogle Scholar
  • 34 Fekete D M. Making sense of making hair cells.  Trends Neurosci. 2000;  23 386
    PubMedGoogle Scholar
  • 35 Bermingham N A, Hassan B A, Price S D et al.. Math1: an essential gene for the generation of inner ear hair cells.  Science. 1999;  284 1837-1841
    CrossrefPubMedGoogle Scholar
  • 36 Shou J, Zheng J L, Gao W Q. Robust generation of new hair cells in the mature mammalian inner ear by adenoviral expression of Hath1.  Mol Cell Neurosci. 2003;  23 169-179
    CrossrefPubMedGoogle Scholar
  • 37 Kawamoto K, Ishimoto S, Minoda R, Brough D E, Raphael Y. Math1 gene transfer generates new cochlear hair cells in mature guinea pigs in vivo.  J Neurosci. 2003;  23 4395-4400
    PubMedGoogle Scholar
  • 38 Izumikawa M, Minoda R, Kawamoto K et al.. Auditory hair cell replacement and hearing improvement by Atoh1 gene therapy in deaf mammals.  Nat Med. 2005;  11 271-276
    CrossrefPubMedGoogle Scholar
  • 39 Chen P, Segil N. p27(Kip1) links cell proliferation to morphogenesis in the developing organ of Corti.  Development. 1999;  126 1581-1590
    PubMedGoogle Scholar
  • 40 Sage C, Huang M, Karimi K et al.. Proliferation of functional hair cells in vivo in the absence of the retinoblastoma protein.  Science. 2005;  307 1114-1118
    CrossrefPubMedGoogle Scholar
  • 41 Mantela J, Jiang Z, Ylikoski J, Fritzsch B, Zacksenhaus E, Pirvola U. The retinoblastoma gene pathway regulates the postmitotic state of hair cells of the mouse inner ear.  Development. 2005;  132 2377-2388
    CrossrefPubMedGoogle Scholar
  • 42 Lowenheim H, Furness D N, Kil J et al.. Gene disruption of p27(Kip1) allows cell proliferation in the postnatal and adult organ of Corti.  Proc Natl Acad Sci USA. 1999;  96 4084-4088
    CrossrefPubMedGoogle Scholar
  • 43 Chen P, Zindy F, Abdala C et al.. Progressive hearing loss in mice lacking the cyclin-dependent kinase inhibitor Ink4d.  Nat Cell Biol. 2003;  5 422-426
    CrossrefPubMedGoogle Scholar
  • 44 Parker M A, Cotanche D A. The potential use of stem cells for cochlear repair.  Audiol Neurootol. 2004;  9 72-80
    CrossrefPubMedGoogle Scholar
  • 45 Leri A, Kajstura J, Anversa P. Cardiac stem cells and mechanisms of myocardial regeneration.  Physiol Rev. 2005;  85 1373-1416
    CrossrefPubMedGoogle Scholar
  • 46 Lumelsky N, Blondel O, Laeng P, Velasco I, Ravin R, McKay R. Differentiation of embryonic stem cells to insulin-secreting structures similar to pancreatic islets.  Science. 2001;  292 1389-1394
    CrossrefPubMedGoogle Scholar
  • 47 Bjorklund L M, Sanchez-Pernaute R, Chung S et al.. Embryonic stem cells develop into functional dopaminergic neurons after transplantation in a Parkinson rat model.  Proc Natl Acad Sci USA. 2002;  99 2344-2349
    CrossrefPubMedGoogle Scholar
  • 48 Kim J H, Auerbach J M, Rodriguez-Gomez J A et al.. Dopamine neurons derived from embryonic stem cells function in an animal model of Parkinson's disease.  Nature. 2002;  418 50-56
    CrossrefPubMedGoogle Scholar
  • 49 Wichterle H, Lieberam I, Porter J A, Jessell T M. Directed differentiation of embryonic stem cells into motor neurons.  Cell. 2002;  110 385-397
    CrossrefPubMedGoogle Scholar
  • 50 Li H, Roblin G, Liu H, Heller S. Generation of hair cells by stepwise differentiation of embryonic stem cells.  Proc Natl Acad Sci USA. 2003;  100 13495-13500
    CrossrefPubMedGoogle Scholar
  • 51 Matsui J I, Parker M A, Ryals B M, Cotanche D A. Regeneration and replacement in the vertebrate inner ear.  Drug Discov Today. 2005;  10 1307-1312
    CrossrefPubMedGoogle Scholar
  • 52 Xiang M, Gan L, Li D et al.. Essential role of POU-domain factor Brn-3c in auditory and vestibular hair cell development.  Proc Natl Acad Sci USA. 1997;  94 9445-9450
    CrossrefPubMedGoogle Scholar
  • 53 Kanda S, Tamada Y, Yoshidome A, Hayashi I, Nishiyama T. Over-expression of bHLH genes facilitate neural formation of mouse embryonic stem (ES) cells in vitro.  Int J Dev Neurosci. 2004;  22 149-156
    PubMedGoogle Scholar
  • 54 Tateya I, Nakagawa T, Iguchi F et al.. Fate of neural stem cells grafted into injured inner ears of mice.  Neuroreport. 2003;  14 1677-1681
    PubMedGoogle Scholar
  • 55 Iguchi F, Nakagawa T, Tateya I et al.. Trophic support of mouse inner ear by neural stem cell transplantation.  Neuroreport. 2003;  14 77-80
    CrossrefPubMedGoogle Scholar
  • 56 Parker M A, Anderson J K, Corliss D A et al.. Expression profile of an operationally-defined neural stem cell clone.  Exp Neurol. 2005;  194 320-332
    CrossrefPubMedGoogle Scholar
  • 57 Kelley M W. Exposing the roots of hair cell regeneration in the ear.  Nat Med. 2003;  9 1257-1259
    PubMedGoogle Scholar
  • 58 Li H, Corrales C E, Edge A, Heller S. Stem cells as therapy for hearing loss.  Trends Mol Med. 2004;  10 309-315
    CrossrefPubMedGoogle Scholar
  • 59 Inzunza J, Sahlen S, Holmberg K et al.. Comparative genomic hybridization and karyotyping of human embryonic stem cells reveals the occurrence of an isodicentric X chromosome after long-term cultivation.  Mol Hum Reprod. 2004;  10 461-466
    CrossrefPubMedGoogle Scholar
  • 60 Draper J S, Smith K, Gokhale P et al.. Recurrent gain of chromosomes 17q and 12 in cultured human embryonic stem cells.  Nat Biotechnol. 2004;  22 53-54
    CrossrefPubMedGoogle Scholar
  • 61 Han J J, Mhatre A N, Wareing M et al.. Transgene expression in the guinea pig cochlea mediated by a lentivirus-derived gene transfer vector.  Hum Gene Ther. 1999;  10 1867-1873
    CrossrefPubMedGoogle Scholar
  • 62 Staecker H, Li D, O'Malley Jr B W, Van De Water T R. Gene expression in the mammalian cochlea: a study of multiple vector systems.  Acta Otolaryngol. 2001;  121 157-163
    CrossrefPubMedGoogle Scholar
  • 63 Lalwani A K, Walsh B J, Carvalho G J, Muzyczka N, Mhatre A N. Expression of adeno-associated virus integrated transgene within the mammalian vestibular organs.  Am J Otol. 1998;  19 390-395
    PubMedGoogle Scholar
  • 64 Wareing M, Mhatre A N, Pettis R et al.. Cationic liposome mediated transgene expression in the guinea pig cochlea.  Hear Res. 1999;  128 61-69
    CrossrefPubMedGoogle Scholar

 Prof.
Karen B AvrahamPh.D. 

Department of Human Molecular Genetics and Biochemistry

Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

Email: karena@post.tau.ac.il

      >