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journal article·2024-08Open access

Gene Electrotransfer via Conductivity‐Clamped Electric Field Focusing Pivots Sensori‐Motor DNA Therapeutics: “A Spoonful of Sugar Helps the Medicine Go Down”

Jeremy L. Pinyon, Georg von Jonquieres, Edward N. Crawford, Amr Al Abed, John M. Power, Matthias Klugmann, Cherylea J. Browne, David M. Housley, Andrew K. Wise, James B. Fallon, Robert K. Shepherd, John Y. Lin, Catherine McMahon, David McAlpine, Catherine S. Birman, Waikong Lai, Ya Lang Enke, Paul M. Carter, James F. Patrick, Robert D. Gay, Corinne Marie, Daniel Scherman, Nigel H. Lovell, Gary D. Housley

Advanced Science· Volume 11· Issue 30
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Source abstract

Abstract

Abstract Viral 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 Ca2+ sensor, achieved photoactivated neuromodulation relevant to the treatment of Parkinson's Disease and other focal brain disorders.
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Research context

OpenAlex topics: CRISPR and Genetic Engineering · Microfluidic and Bio-sensing Technologies · Advanced biosensing and bioanalysis techniques

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Translational Neuroscience Facility Department of Physiology School of Biomedical Sciences Graduate School of Biomedical Engineering Tyree Institute for Health Engineering (IHealthE) UNSW Sydney NSW 2052 Australia

Charles Perkins Centre School of Medical Sciences Faculty of Medicine and Health University of Sydney Sydney NSW 2006 Australia

Medical Sciences School of Science Western Sydney University Sydney NSW 2560 Australia

Bionics Institute 384–388 Albert Street East Melbourne VIC 3002 Australia

Medical Bionics Department of Otolaryngology University of Melbourne Melbourne VIC 3002 Australia

Tasmanian School of Medicine University of Tasmania Hobart TAS 7001 Australia

Faculty of Medicine and Health Sciences The Hearing Hub Macquarie University Sydney 2109 Australia

Faculty of Medicine and Health University of Sydney Sydney NSW 2006 Australia

Department of Otolaryngology Royal Prince Alfred Hospital Camperdown NSW 2050 Australia

NextSense Royal Institute of Deaf and Blind Children Gladesville NSW 2111 Australia

Cochlear Limited Macquarie University University Avenue Macquarie Park NSW 2109 Australia

CNRS, Inserm, UTCBS Université Paris Cité Paris F‐75006 France

Chimie ParisTech Université PSL Paris 75005 France

Fondation Maladies Rares 96 rue Didot Paris 75014 France

Funding

Australian Research Council · Macquarie University · National Health and Medical Research Council

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