Computational modeling for precision targeting of conductivity-clamped gene electrotransfer within the striatum of...

Objective.Bionic array-directed gene electrotransfer (GET) is an emerging technology for precision 'vector-free' transfection of naked delivery of nucleic acid (DNA/mRNA) to target tissues, utilizing electro-lens focusing of a pulsed electric field. The efficiency of this translocation of naked polyanionic macromolecular nucleic acids (NAs) to the plasma membrane is greatly enhanced by reducing tissue conductivity ('conductivity-clamping') CC by the displacement of extracellular ionic species using a low-conductivity carrier (sucrose). This increases the electric field strength, minimizes the charge transfer, and significantly enhances gene transfection.Approach.T1 and diffusion weighted imaging clinical magnetic resonance imaging data, along with spatiotemporal mapping of sucrose-mediated ion CC in the guinea pig brain, enabled computational modeling of electric field manipulation. The scalable model was informed byin vitrosingle capacitive discharge GET of green fluorescent protein reporter plasmid DNA in HEK293 cells, andin vivoCC in the guinea pig brain striatum where spatiotemporal mapping of local tissue conductivity reduction was recorded proximal to the infusion site and at distance.Main results.These data enabled the prediction of the shape and volume of the transfection zone with respect to the GET pulse current amplitude, electrode orientation, and current steering between the electrodes. The predicted suprathreshold brain tissue volume for GET in the striatal region of the human brain increases by 130% with CC.Significance.This experimentally refined model was translated into the human brain to enable the integration of precise 3D targeting of NA therapeutics for directing gene-based treatments, such as the striatal basal ganglia target for Parkinson's disease.