Gene Electrotransfer via Conductivity-Clamped Electric Field Focusing Pivots Sensori-Motor DNA Therapeutics: "A Spoonful of Sugar Helps the Medicine Go Down".

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dc.contributor.authorPinyon, Jeremy L
dc.contributor.authorvon Jonquieres, Georg
dc.contributor.authorCrawford, Edward N
dc.contributor.authorAbed, Amr Al
dc.contributor.authorPower, John M
dc.contributor.authorKlugmann, Matthias
dc.contributor.authorBrowne, Cherylea J
dc.contributor.authorHousley, David M
dc.contributor.authorWise, Andrew K
dc.contributor.authorFallon, James B
dc.contributor.authorShepherd, Robert K
dc.contributor.authorLin, John Y
dc.contributor.authorMcMahon, Catherine
dc.contributor.authorMcAlpine, David
dc.contributor.authorBirman, Catherine S
dc.contributor.authorLai, Waikong
dc.contributor.authorEnke, Ya Lang
dc.contributor.authorCarter, Paul M
dc.contributor.authorPatrick, James F
dc.contributor.authorGay, Robert D
dc.contributor.authorMarie, Corinne
dc.contributor.authorScherman, Daniel
dc.contributor.authorLovell, Nigel H
dc.contributor.authorHousley, Gary D
dc.date.accessioned2024-08-15T00:27:18Z
dc.date.available2024-08-15T00:27:18Z
dc.date.issued2024-06-14
dc.description.abstractViral vectors and lipofection-based gene therapies have dispersion-dependent transduction/transfection profiles that thwart precise targeting. The study describes the development of focused close-field gene electrotransfer (GET) technology, refining spatial control of gene expression. Integration of fluidics for precise delivery of "naked" plasmid deoxyribonucleic acid (DNA) in sucrose carrier within the focused electric field enables negative biasing of near-field conductivity ("conductivity-clamping"-CC), increasing the efficiency of plasma membrane molecular translocation. This enables titratable gene delivery with unprecedently low charge transfer. The clinic-ready bionics-derived CC-GET device achieved neurotrophin-encoding miniplasmid DNA delivery to the cochlea to promote auditory nerve regeneration; validated in deafened guinea pig and cat models, leading to improved central auditory tuning with bionics-based hearing. The performance of CC-GET is evaluated in the brain, an organ problematic for pulsed electric field-based plasmid DNA delivery, due to high required currents causing Joule-heating and damaging electroporation. Here CC-GET enables safe precision targeting of gene expression. In the guinea pig, reporter expression is enabled in physiologically critical brainstem regions, and in the striatum (globus pallidus region) delivery of a red-shifted channelrhodopsin and a genetically-encoded Ca sensor, achieved photoactivated neuromodulation relevant to the treatment of Parkinson's Disease and other focal brain disorders.
dc.description.sponsorshipElla Trang is thanked for her contributions to supporting the cat auditory nerve regeneration study. Freddy Dueck from Cochlear Ltd is thanked for his support in the development of the clinical CC-GET gene delivery array. Lily Pearson is thanked for her assistance with cell culture imaging. Australian Research Council (ARC) Grants: LP0992098 (GH; Cochlear Ltd. Industry Partner–JFP); LP140101008 (G.H., N.L., M.K., Cochlear Ltd. Industry Partner – PC), and DP151014754 (G.H., N.L., M.K.). National Health & Medical Research Council (NHMRC) grants APP1048764 (M.K.,G.H.), APP1189113 (G.H., J.L.P.,G.J., M.K.,N.L.), APP1091646 (G.H., R.S.,N.L., M.K., C.Mc., C.S.B., A.W., J.F., Cochlear Ltd. Partner – J.F.P., P.C.,Y.L.E.), APP2013285 (G.H., N.L., M.K., A.A., G.J., J.L.P., D.S.). Passe & Williams Foundation supplementary (G.H., R.S., N.L., M.K., C.Mc., C.S.B.,A.W., J.F.) and conjoint grant (G.H., C.S.B., W.L., J.L.P., D.Mc.) funding schemes. Supplementary funding from UNSW Sydney, Macquarie University, NextSense, and NHMRC development grant–linked funding and in-kind support from Cochlear Ltd. as an Industry Partner. Open access publishing facilitated by University of New South Wales, as part of the Wiley - University of New South Wales agreement via the Council of Australian University Librarians.
dc.identifier.citationPinyon JL, von Jonquieres G, Crawford EN, Abed AA, Power JM, Klugmann M, Browne CJ, Housley DM, Wise AK, Fallon JB, Shepherd RK, Lin JY, McMahon C, McAlpine D, Birman CS, Lai W, Enke YL, Carter PM, Patrick JF, Gay RD, Marie C, Scherman D, Lovell NH, Housley GD. Gene Electrotransfer via Conductivity-Clamped Electric Field Focusing Pivots Sensori-Motor DNA Therapeutics: "A Spoonful of Sugar Helps the Medicine Go Down". Adv Sci (Weinh). 2024 Aug;11(30):e2401392. doi: 10.1002/advs.202401392. Epub 2024 Jun 14. PMID: 38874431; PMCID: PMC11321635.
dc.identifier.urihttps://repository.bionicsinstitute.org/handle/123456789/462
dc.language.isoen
dc.publisherAdvanced Science News
dc.subjectCNS electrotransfer
dc.subjectCNS neuromodulation
dc.subjectnerve regeneration
dc.subjectnonviral gene augmentation therapy
dc.subjectprecision gene delivery
dc.titleGene Electrotransfer via Conductivity-Clamped Electric Field Focusing Pivots Sensori-Motor DNA Therapeutics: "A Spoonful of Sugar Helps the Medicine Go Down".
dc.typeArticle
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