title: Viability of long-term gene therapy in the cochlea.
abstract: Gene therapy has been investigated as a way to introduce a variety of genes to treat neurological disorders. An important clinical consideration is its long-term effectiveness. This research aims to study the long-term expression and effectiveness of gene therapy in promoting spiral ganglion neuron survival after deafness. Adenoviral vectors modified to express brain derived neurotrophic factor or neurotrophin-3 were unilaterally injected into the guinea pig cochlea one week post ototoxic deafening. After six months, persistence of gene expression and significantly greater neuronal survival in neurotrophin-treated cochleae compared to the contralateral cochleae were observed. The long-term gene expression observed indicates that gene therapy is potentially viable; however the degeneration of the transduced cells as a result of the original ototoxic insult may limit clinical effectiveness. With further research aimed at transducing stable cochlear cells, gene therapy may be an efficacious way to introduce neurotrophins to promote neuronal survival after hearing loss.
authors.affiliation: 1] Bionics Institute, East Melbourne, Victoria, Australia [2] Department of Otolaryngology, University of Melbourne, East Melbourne, Victoria, Australia.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Atkinson
authors.affiliation: 1] Bionics Institute, East Melbourne, Victoria, Australia [2] Department of Otolaryngology, University of Melbourne, East Melbourne, Victoria, Australia [3] Department of Medical Bionics, University of Melbourne, East Melbourne, Victoria, Australia.
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Wise
authors.affiliation: Bionics Institute, East Melbourne, Victoria, Australia.
authors.forename: Brianna O
authors.initials: BO
authors.lastname: Flynn
authors.affiliation: 1] Bionics Institute, East Melbourne, Victoria, Australia [2] Department of Audiology and Speech Pathology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Bryony A
authors.initials: BA
authors.lastname: Nayagam
authors.affiliation: 1] Bionics Institute, East Melbourne, Victoria, Australia [2] Department of Otolaryngology, University of Melbourne, East Melbourne, Victoria, Australia [3] Department of Medical Bionics, University of Melbourne, East Melbourne, Victoria, Australia.
authors.forename: Rachael T
authors.initials: RT
authors.lastname: Richardson
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D003051:Cochlea / Q000378:metabolism*; D003638:Deafness / Q000235:genetics / Q000628:therapy; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D018014:Gene Transfer Techniques; D017930:Genes, Reporter; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics; D008297:Male; D009414:Nerve Growth Factors / Q000235:genetics; D020933:Neurotrophin 3 / Q000235:genetics; D009925:Organ of Corti / Q000378:metabolism / Q000473:pathology; D013136:Spiral Ganglion / Q000378:metabolism / Q000473:pathology; D013552:Swine; D013997:Time Factors
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D020933:Neurotrophin 3
references.citation: Exp Neurol. 2010 Jun;223(2):464-72
references.pmid: 20109446
references.citation: Exp Neurol. 2008 Dec;214(2):193-200
references.pmid: 18773894
references.citation: J Comp Neurol. 2005 Jun 27;487(2):147-65
references.pmid: 15880560
references.citation: J Comp Neurol. 2005 May 30;486(2):145-58
references.pmid: 15844207
references.citation: PLoS One. 2011 Apr 15;6(4):e18733
references.pmid: 21525998
references.citation: Mol Ther. 2008 Mar;16(3):474-80
references.pmid: 18180779
references.citation: Lancet Neurol. 2011 Apr;10(4):309-19
references.pmid: 21419704
references.citation: Mol Ther. 2006 Oct;14(4):564-70
references.pmid: 16829205
references.citation: Otolaryngol Head Neck Surg. 1997 Sep;117(3 Pt 1):220-8
references.pmid: 9334769
references.citation: Science. 2002 Oct 11;298(5592):425-9
references.pmid: 12376704
references.citation: Audiol Neurootol. 2008;13(2):86-96
references.pmid: 18057872
references.citation: Eur J Neurosci. 2007 Jul;26(2):510-22
references.pmid: 17650121
references.citation: Nat Med. 2005 Mar;11(3):271-6
references.pmid: 15711559
references.citation: Biomaterials. 2009 May;30(13):2614-24
references.pmid: 19178943
references.citation: Hear Res. 2011 Aug;278(1-2):69-76
references.pmid: 21557994
references.citation: Mol Ther. 2010 Jun;18(6):1111-22
references.pmid: 20216530
references.citation: Neuroreport. 1999 Jul 13;10(10):2067-71
references.pmid: 10424676
references.citation: J Clin Invest. 2011 Jun;121(6):2160-8
references.pmid: 21606598
references.citation: J Neurosci Res. 2003 Mar 15;71(6):785-90
references.pmid: 12605404
references.citation: N Engl J Med. 2008 May 22;358(21):2240-8
references.pmid: 18441370
references.citation: Neuron. 2012 Jul 26;75(2):283-93
references.pmid: 22841313
references.citation: Adv Mater. 2012 Jul 3;24(25):3362-6
references.pmid: 22610659
references.citation: Neurotherapeutics. 2011 Oct;8(4):774-87
references.pmid: 21904788
references.citation: PLoS One. 2012;7(1):e30577
references.pmid: 22299045
references.citation: J Assoc Res Otolaryngol. 2009 Sep;10(3):355-67
references.pmid: 19365690
references.citation: Gene. 2000 May 2;248(1-2):223-31
references.pmid: 10806367
references.citation: PLoS One. 2012;7(12):e52338
references.pmid: 23284995
references.citation: Laryngoscope. 1978 Aug;88(8 Pt 1):1231-46
references.pmid: 672357
references.citation: Ann Otol Rhinol Laryngol. 1989 Jun;98(6):411-6
references.pmid: 2729822