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Neurotrophin gene augmentation by electrotransfer to improve cochlear implant hearing outcomes.
Hear Res 2019; 380:137-149HR

Abstract

This Review outlines the development of DNA-based therapeutics for treatment of hearing loss, and in particular, considers the potential to utilize the properties of recombinant neurotrophins to improve cochlear auditory (spiral ganglion) neuron survival and repair. This potential to reduce spiral ganglion neuron death and indeed re-grow the auditory nerve fibres has been the subject of considerable pre-clinical evaluation over decades with the view of improving the neural interface with cochlear implants. This provides the context for discussion about the development of a novel means of using cochlear implant electrode arrays for gene electrotransfer. Mesenchymal cells which line the cochlear perilymphatic compartment can be selectively transfected with (naked) plasmid DNA using array - based gene electrotransfer, termed 'close-field electroporation'. This technology is able to drive expression of brain derived neurotrophic factor (BDNF) in the deafened guinea pig model, causing re-growth of the spiral ganglion peripheral neurites towards the mesenchymla cells, and hence into close proximity with cochlear implant electrodes within scala tympani. This was associated with functional enhancement of the cochlear implant neural interface (lower neural recruitment thresholds and expanded dynamic range, measured using electrically - evoked auditory brainstem responses). The basis for the efficiency of close-field electroporation arises from the compression of the electric field in proximity to the ganged cochlear implant electrodes. The regions close to the array with highest field strength corresponded closely to the distribution of bioreporter cells (adherent human embryonic kidney (HEK293)) expressing green fluorescent reporter protein (GFP) following gene electrotransfer. The optimization of the gene electrotransfer parameters using this cell-based model correlated closely with in vitro and in vivo cochlear gene delivery outcomes. The migration of the cochlear implant electrode array-based gene electrotransfer platform towards a clinical trial for neurotrophin-based enhancement of cochlear implants is supported by availability of a novel regulatory compliant mini-plasmid DNA backbone (pFAR4; plasmid Free of Antibiotic Resistance v.4) which could be used to package a 'humanized' neurotrophin expression cassette. A reporter cassette packaged into pFAR4 produced prominent GFP expression in the guinea pig basal turn perilymphatic scalae. More broadly, close-field gene electrotransfer may lend itself to a spectrum of potential DNA therapeutics applications benefitting from titratable, localised, delivery of naked DNA, for gene augmentation, targeted gene regulation, or gene substitution strategies.

Authors+Show Affiliations

Translational Neuroscience Facility & Department of Physiology, School of Medical Sciences, UNSW Sydney, NSW, Australia.Translational Neuroscience Facility & Department of Physiology, School of Medical Sciences, UNSW Sydney, NSW, Australia.Translational Neuroscience Facility & Department of Physiology, School of Medical Sciences, UNSW Sydney, NSW, Australia.Translational Neuroscience Facility & Department of Physiology, School of Medical Sciences, UNSW Sydney, NSW, Australia.The Graduate School of Biomedical Engineering, UNSW Sydney, NSW, Australia.The Graduate School of Biomedical Engineering, UNSW Sydney, NSW, Australia.Translational Neuroscience Facility & Department of Physiology, School of Medical Sciences, UNSW Sydney, NSW, Australia.Bionics Institute, St Vincent's Hospital, Melbourne, Australia; Department of Medical Bionics, University of Melbourne, Melbourne, Australia; Department of Otolaryngology, University of Melbourne, Melbourne, Australia.Bionics Institute, St Vincent's Hospital, Melbourne, Australia; Department of Medical Bionics, University of Melbourne, Melbourne, Australia; Department of Otolaryngology, University of Melbourne, Melbourne, Australia.Bionics Institute, St Vincent's Hospital, Melbourne, Australia; Department of Medical Bionics, University of Melbourne, Melbourne, Australia; Department of Otolaryngology, University of Melbourne, Melbourne, Australia.Department of Otolaryngology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia; The Sydney Cochlear Implant Centre, Royal Institute of Deaf and Blind Children, Gladesville, NSW, Australia; Department of Linguistics, Facility of Human Sciences, Macquarie University, North Ryde, Australia.Department of Otolaryngology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia.The Hearing Hub, Macquarie University, Sydney, Australia; The HEARing Cooperative Research Centre, Melbourne, Australia.The Hearing Hub, Macquarie University, Sydney, Australia; The HEARing Cooperative Research Centre, Melbourne, Australia.Cochlear Ltd, Sydney, Australia.Cochlear Ltd, Sydney, Australia.Cochlear Ltd, Sydney, Australia.Ear Institute, University College London, London, United Kingdom.Laboratory of Chemical and Biological Technologies for Health, Université Paris Descartes, Sorbonne-Paris-Cité, F-75006, Paris, France; CNRS, UTCBS UMR 8258, F-75006, Paris, France; Chimie ParisTech, PSL Research University, UTCBS, F-75005, Paris, France; INSERM, UTCBS U 1267, F-75006, Paris, France.Laboratory of Chemical and Biological Technologies for Health, Université Paris Descartes, Sorbonne-Paris-Cité, F-75006, Paris, France; CNRS, UTCBS UMR 8258, F-75006, Paris, France; Chimie ParisTech, PSL Research University, UTCBS, F-75005, Paris, France; INSERM, UTCBS U 1267, F-75006, Paris, France.Translational Neuroscience Facility & Department of Physiology, School of Medical Sciences, UNSW Sydney, NSW, Australia. Electronic address: g.housley@unsw.edu.au.

Pub Type(s)

Journal Article
Review

Language

eng

PubMed ID

31301514

Citation

Pinyon, Jeremy L., et al. "Neurotrophin Gene Augmentation By Electrotransfer to Improve Cochlear Implant Hearing Outcomes." Hearing Research, vol. 380, 2019, pp. 137-149.
Pinyon JL, von Jonquieres G, Crawford EN, et al. Neurotrophin gene augmentation by electrotransfer to improve cochlear implant hearing outcomes. Hear Res. 2019;380:137-149.
Pinyon, J. L., von Jonquieres, G., Crawford, E. N., Duxbury, M., Al Abed, A., Lovell, N. H., ... Housley, G. D. (2019). Neurotrophin gene augmentation by electrotransfer to improve cochlear implant hearing outcomes. Hearing Research, 380, pp. 137-149. doi:10.1016/j.heares.2019.06.002.
Pinyon JL, et al. Neurotrophin Gene Augmentation By Electrotransfer to Improve Cochlear Implant Hearing Outcomes. Hear Res. 2019 Sep 1;380:137-149. PubMed PMID: 31301514.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Neurotrophin gene augmentation by electrotransfer to improve cochlear implant hearing outcomes. AU - Pinyon,Jeremy L, AU - von Jonquieres,Georg, AU - Crawford,Edward N, AU - Duxbury,Mayryl, AU - Al Abed,Amr, AU - Lovell,Nigel H, AU - Klugmann,Matthias, AU - Wise,Andrew K, AU - Fallon,James B, AU - Shepherd,Robert K, AU - Birman,Catherine S, AU - Lai,Waikong, AU - McAlpine,David, AU - McMahon,Catherine, AU - Carter,Paul M, AU - Enke,Ya Lang, AU - Patrick,James F, AU - Schilder,Anne G M, AU - Marie,Corinne, AU - Scherman,Daniel, AU - Housley,Gary D, Y1 - 2019/06/21/ PY - 2019/02/06/received PY - 2019/06/07/revised PY - 2019/06/12/accepted PY - 2019/7/14/pubmed PY - 2019/7/14/medline PY - 2019/7/14/entrez KW - Auditory nerve fibre regeneration KW - Bionic array directed gene electrotransfer KW - Brain derived neurotrophic factor KW - Gene therapy KW - Neurotrophin-3 KW - Sensorineural hearing loss SP - 137 EP - 149 JF - Hearing research JO - Hear. Res. VL - 380 N2 - This Review outlines the development of DNA-based therapeutics for treatment of hearing loss, and in particular, considers the potential to utilize the properties of recombinant neurotrophins to improve cochlear auditory (spiral ganglion) neuron survival and repair. This potential to reduce spiral ganglion neuron death and indeed re-grow the auditory nerve fibres has been the subject of considerable pre-clinical evaluation over decades with the view of improving the neural interface with cochlear implants. This provides the context for discussion about the development of a novel means of using cochlear implant electrode arrays for gene electrotransfer. Mesenchymal cells which line the cochlear perilymphatic compartment can be selectively transfected with (naked) plasmid DNA using array - based gene electrotransfer, termed 'close-field electroporation'. This technology is able to drive expression of brain derived neurotrophic factor (BDNF) in the deafened guinea pig model, causing re-growth of the spiral ganglion peripheral neurites towards the mesenchymla cells, and hence into close proximity with cochlear implant electrodes within scala tympani. This was associated with functional enhancement of the cochlear implant neural interface (lower neural recruitment thresholds and expanded dynamic range, measured using electrically - evoked auditory brainstem responses). The basis for the efficiency of close-field electroporation arises from the compression of the electric field in proximity to the ganged cochlear implant electrodes. The regions close to the array with highest field strength corresponded closely to the distribution of bioreporter cells (adherent human embryonic kidney (HEK293)) expressing green fluorescent reporter protein (GFP) following gene electrotransfer. The optimization of the gene electrotransfer parameters using this cell-based model correlated closely with in vitro and in vivo cochlear gene delivery outcomes. The migration of the cochlear implant electrode array-based gene electrotransfer platform towards a clinical trial for neurotrophin-based enhancement of cochlear implants is supported by availability of a novel regulatory compliant mini-plasmid DNA backbone (pFAR4; plasmid Free of Antibiotic Resistance v.4) which could be used to package a 'humanized' neurotrophin expression cassette. A reporter cassette packaged into pFAR4 produced prominent GFP expression in the guinea pig basal turn perilymphatic scalae. More broadly, close-field gene electrotransfer may lend itself to a spectrum of potential DNA therapeutics applications benefitting from titratable, localised, delivery of naked DNA, for gene augmentation, targeted gene regulation, or gene substitution strategies. SN - 1878-5891 UR - https://www.unboundmedicine.com/medline/citation/31301514/Neurotrophin_gene_augmentation_by_electrotransfer_to_improve_cochlear_implant_hearing_outcomes L2 - https://linkinghub.elsevier.com/retrieve/pii/S0378-5955(19)30044-9 DB - PRIME DP - Unbound Medicine ER -