title: Development of a cell-based treatment for long-term neurotrophin expression and spiral ganglion neuron survival.
abstract: Spiral ganglion neurons (SGNs), the target cells of the cochlear implant, undergo gradual degeneration following loss of the sensory epithelium in deafness. The preservation of a viable population of SGNs in deafness can be achieved in animal models with exogenous application of neurotrophins such as brain-derived neurotrophic factor (BDNF) and neurotrophin-3. For translation into clinical application, a suitable delivery strategy that provides ongoing neurotrophic support and promotes long-term SGN survival is required. Cell-based neurotrophin treatment has the potential to meet the specific requirements for clinical application, and we have previously reported that Schwann cells genetically modified to express BDNF can support SGN survival in deafness for 4 weeks. This study aimed to investigate various parameters important for the development of a long-term cell-based neurotrophin treatment to support SGN survival. Specifically, we investigated different (i) cell types, (ii) gene transfer methods and (iii) neurotrophins, in order to determine which variables may provide long-term neurotrophin expression and which, therefore, may be the most effective for supporting long-term SGN survival in vivo. We found that fibroblasts that were nucleofected to express BDNF provided the most sustained neurotrophin expression, with ongoing BDNF expression for at least 30 weeks. In addition, the secreted neurotrophin was biologically active and elicited survival effects on SGNs in vitro. Nucleofected fibroblasts may therefore represent a method for safe, long-term delivery of neurotrophins to the deafened cochlea to support SGN survival in deafness.
authors.affiliation: Bionics Institute, Melbourne, Australia.
authors.forename: M P
authors.initials: MP
authors.lastname: Zanin
authors.affiliation: School of Anatomy, Physiology and Human Biology, The University of Western Australia, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Hellström
authors.affiliation: Bionics Institute, Melbourne, Australia; Department of Medical Bionics, University of Melbourne, Australia.
authors.forename: R K
authors.initials: RK
authors.lastname: Shepherd
authors.affiliation: School of Anatomy, Physiology and Human Biology, The University of Western Australia, Australia.
authors.forename: A R
authors.initials: AR
authors.lastname: Harvey
authors.affiliation: Bionics Institute, Melbourne, Australia; Department of Medical Bionics, University of Melbourne, Australia. Electronic address: lgillespie@bionicsinstitute.org.
authors.forename: L N
authors.initials: LN
authors.lastname: Gillespie
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D018929:Cell Culture Techniques; D002470:Cell Survival / Q000502:physiology; D064987:Cell- and Tissue-Based Therapy / Q000379:methods*; D018920:Coculture Techniques; D005347:Fibroblasts / Q000502:physiology*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000502:physiology*; D020933:Neurotrophin 3; D051381:Rats; D012583:Schwann Cells / Q000502:physiology; D012584:Sciatic Nerve / Q000502:physiology; D013136:Spiral Ganglion / Q000502:physiology*; D014162:Transfection
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C000595808:NTF3 protein, human; D009414:Nerve Growth Factors; D020933:Neurotrophin 3; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins
keywords: lentivirus; lipofection; neurotrophin; nucleofection; sensorineural hearing loss; spiral ganglion neuron