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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Date
2024-06-14
Journal Title
Journal ISSN
Volume Title
Publisher
Advanced Science News
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 Ca sensor, achieved photoactivated neuromodulation relevant to the treatment of Parkinson's Disease and other focal brain disorders.
Description
Keywords
CNS electrotransfer, CNS neuromodulation, nerve regeneration, nonviral gene augmentation therapy, precision gene delivery
Citation
Pinyon 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.