Gene Electrotransfer via Conductivity‐Clamped Electric Field Focusing Pivots Sensori‐Motor DNA Therapeutics: “A Spoonful of Sugar Helps the Medicine Go Down”
Year: 2024
Type: article
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.
Source: Advanced Science
Authors: 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
Institutions: The University of Sydney, UNSW Sydney, Western Sydney University, Bionics Institute, The University of Melbourne, University of Tasmania, Macquarie University, NextSense, Royal Prince Alfred Hospital, Centre National de la Recherche Scientifique, Chimie ParisTech - PSL, Inserm, Université Paris Cité, Université Paris Sciences et Lettres, Unité de Technologies Chimiques et Biologiques pour la Santé, Fondation Maladies Rares
Language: English
Subfield: Biotechnology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,120
Awards: Gene therapy to enhance auditory prosthesis performance for cochlear implants, Restoring hearing by gene electrotransfer – based enablement of auditory neurons to transduce sound, G497455292, Bionic-array Directed Gene Electrotransfer for Treating Focal Brain Disorders, Closing the neural gap in the bionic ear, Electric field effects on cochlear tissues, BDNF delivery to motor neurones in a rat model that impairs the grasping action
OpenAlex ID: W4399673440