Differential effects of AAV.BDNF and AAV.Ntf3 in the deafened adult guinea pig ear.
Cochlear hair cell loss results in secondary regression of peripheral auditory fibers (PAFs) and loss of spiral ganglion neurons (SGNs). The performance of cochlear implants (CI) in rehabilitating hearing depends on survival of SGNs. Here we compare the effects of adeno-associated virus vectors with neurotrophin gene inserts, AAV.BDNF and AAV.Ntf3, on guinea pig ears deafened systemically (kanamycin and furosemide) or locally (neomycin). AAV.BDNF or AAV.Ntf3 was delivered to the guinea pig cochlea one week following deafening and ears were assessed morphologically 3 months later. At that time, neurotrophins levels were not significantly elevated in the cochlear fluids, even though in vitro and shorter term in vivo experiments demonstrate robust elevation of neurotrophins with these viral vectors. Nevertheless, animals receiving these vectors exhibited considerable re-growth of PAFs in the basilar membrane area. In systemically deafened animals there was a negative correlation between the presence of differentiated supporting cells and PAFs, suggesting that supporting cells influence the outcome of neurotrophin over-expression aimed at enhancing the cochlear neural substrate. Counts of SGN in Rosenthal's canal indicate that BDNF was more effective than NT-3 in preserving SGNs. The results demonstrate that a transient elevation in neurotrophin levels can sustain the cochlear neural substrate in the long term.
Kresge Hearing Research Institute, Department of Otolaryngology - Head and Neck Surgery, The University of Michigan, Ann Arbor, MI, USA.
Cameron L
CL
Budenz
Kresge Hearing Research Institute, Department of Otolaryngology - Head and Neck Surgery, The University of Michigan, Ann Arbor, MI, USA.
Hiu Tung
HT
Wong
Kresge Hearing Research Institute, Department of Otolaryngology - Head and Neck Surgery, The University of Michigan, Ann Arbor, MI, USA.
Donald L
DL
Swiderski
Kresge Hearing Research Institute, Department of Otolaryngology - Head and Neck Surgery, The University of Michigan, Ann Arbor, MI, USA.
Seiji B
SB
Shibata
Kresge Hearing Research Institute, Department of Otolaryngology - Head and Neck Surgery, The University of Michigan, Ann Arbor, MI, USA.
Bryan E
BE
Pfingst
Kresge Hearing Research Institute, Department of Otolaryngology - Head and Neck Surgery, The University of Michigan, Ann Arbor, MI, USA.
Yehoash
Y
Raphael
D000375:Aging; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000627:therapeutic use*; D002470:Cell Survival; D003470:Culture Media; D003638:Deafness / Q000473:pathology / Q000628:therapy*; D000229:Dependovirus / Q000378:metabolism*; D004423:Ear / Q000473:pathology*; D004848:Epithelium / Q000378:metabolism / Q000473:pathology; D005260:Female; D005822:Genetic Vectors; D006168:Guinea Pigs; D007760:Labyrinth Supporting Cells / Q000378:metabolism / Q000473:pathology; D008297:Male; D009355:Neomycin; D020933:Neurotrophin 3 / Q000235:genetics / Q000627:therapeutic use*; D010498:Perilymph / Q000378:metabolism; D013136:Spiral Ganglion / Q000378:metabolism / Q000473:pathology; D016896:Treatment Outcome
D019208:Brain-Derived Neurotrophic Factor; D003470:Culture Media; D020933:Neurotrophin 3; D009355:Neomycin