Cochlear implant close-field electroporation

Abstract

Applications for gene therapy that depend upon localization and control of gene expression are challenged by the mode for gene delivery. Viral vectors inherently suffer spread of the viral particles, as does liposome-based gene transfer. Similarly conventional "open-field" electroporation (OFE) achieves gene electrotransfer of naked plasmid DNA injected generally into the target tissue bymeans of a brief train of high-voltage electrical pulses creating a quasi-uniform electric field. The targeting of the gene transferwithOFE can be controlled to some extent by the placement of the electrodes in the tissue and the volume of injectedDNA.In this chapter the application of "close-field" electroporation (CFE) is described, where a gene delivery probe is used for highly localized and controlled gene electrotransfer. CFE arose from use of cochlear implant electrode arrays, designed for spatially constrained electrical stimulation of the primary auditory neurons in the cochlea, where the array was reconfigured to provide electric field focusing that produced electric field strengths sufficient for gene delivery in the domain close to the bionic array using applied voltages considerably below that normally required for conventional electroporation. CFE has proved to be a highly robust and efficient means for targeting small tissue regions (hundreds of um2 - to several mm2) for efficient gene delivery, where the shape of the region of the tissue targeted for gene delivery can be controlled by varying the electric field shape around the bionic array andwhere near "dial-up" control of the delivery of the DNA payload can be achieved by varying the pulse parameters. The CFE gene electrotransfer platform has been successful in establishing a proof of principle for local neurotrophin gene therapy in the cochlea that regenerates primary auditory neuron dendrites in a deafened animal model, improving cochlear implant performance for hearing. The ability to control the distribution of the electric field around the bionic electrode array to deliver titrated local gene electrotransfer suggests that CFE could have broad application for gene therapy.