Close-Field Electroporation Gene Delivery Using the Cochlear Implant Electrode Array Enhances the Bionic Ear

Neurotrophin gene delivery, achieved by “close-field” electroporation of mesenchymal cells adjacent to the cochlear implant, improved hearing in deafened guinea pigs. Can You Hear Me Now? Hearing loss affects millions worldwide. Sensorineural hearing loss, in particular, typically follows the loss of cochlear hair cells—specialized cells in the inner ear that help convert acoustic vibrations into nerve impulses, a process that allows you to hear. Cochlear implants, or “bionic ears,” have been incredibly useful for deaf individuals; however, improvements in sound quality and range of environments where the implant can be used are desired. In this issue, Pinyon and colleagues worked to improve upon existing implants by simultaneously delivering a neurotrophic factor that can regenerate auditory nerves and, in turn, restore hearing. The authors coined their approach “close-field electroporation. ” An electrode array inserted into the cochlea of guinea pigs delivered brief, intense electrical pulses to surrounding tissue. This led to electroporation—basically, a temporary opening of the cell membrane—which allowed passage of genetic material into the mesenchymal cells lining the scala tympani. Once inside the cells’ nuclei, the gene construct produced brain-derived neurotrophic factor (BDNF), a protein in humans that is considered to be a nerve growth factor. Electroporation-mediated BDNF gene delivery drove regeneration of neurites in the cochlea, leading to restoration of hearing in a deafened guinea pig model (animals with hair cells destroyed). Because cochlear implants are already routinely used in patients, with further optimization of electroporation, it is possible that including gene therapy could restore hearing loss and improve the quality of hearing in deaf individuals. The cochlear implant is the most successful bionic prosthesis and has transformed the lives of people with profound hearing loss. However, the performance of the “bionic ear” is still largely constrained by the neural interface itself. Current spread inherent to broad monopolar stimulation of the spiral ganglion neuron somata obviates the intrinsic tonotopic mapping of the cochlear nerve. We show in the guinea pig that neurotrophin gene therapy integrated into the cochlear implant improves its performance by stimulating spiral ganglion neurite regeneration. We used the cochlear implant electrode array for novel “close-field” electroporation to transduce mesenchymal cells lining the cochlear perilymphatic canals with a naked complementary DNA gene construct driving expression of brain-derived neurotrophic factor (BDNF) and a green fluorescent protein (GFP) reporter. The focusing of electric fields by particular cochlear implant electrode configurations led to surprisingly efficient gene delivery to adjacent mesenchymal cells. The resulting BDNF expression stimulated regeneration of spiral ganglion neurites, which had atrophied 2 weeks after ototoxic treatment, in a bilateral sensorineural deafness model. In this model, delivery of a control GFP-only vector failed to restore neuron structure, with atrophied neurons indistinguishable from unimplanted cochleae. With BDNF therapy, the regenerated spiral ganglion neurites extended close to the cochlear implant electrodes, with localized ectopic branching. This neural remodeling enabled bipolar stimulation via the cochlear implant array, with low stimulus thresholds and expanded dynamic range of the cochlear nerve, determined via electrically evoked auditory brainstem responses. This development may broadly improve neural interfaces and extend molecular medicine applications.