Researchers have come up with an unusual variation of the theme of drug-device combinations. They have used cochlear implants as electroporation devices to enable gene therapy during implantation, which in turn stimulated nerve outgrowth that allowed the implant to perform better.
The team published their animal studies in the April 24, 2014, issue of Science Translational Medicine.
Electrical current can be used to briefly increase the permeability of cell membranes for gene delivery. Companies like Inovio Pharmaceuticals Inc., Maxcyte Inc. and Oncosec Medical Inc. use electroporation to deliver DNA, for vaccination or therapeutic purposes. (See BioWorld Today, Aug. 12, 2011.)
And electrical current is also used for another, heretofore separate purpose in medicine: in neural prostheses that use direct electrical stimulation to communicate directly with the brain, which uses electrical impulses as its information processing currency.
Cochlear implants, which replace the cells in the middle ear that sense sound and can restore hearing to profoundly deaf individuals, were the first such neuroprosthesis to make it into routine clinical use.
That they work at all seems, at first glance (or whisper), rather fantastic – the first cochlear implant replaced roughly 10,000 outer hair cells with a single electrode. Modern devices have between one and two dozen such electrodes.
Cochlear implants might work even better, however, if they were able to make better contact with the auditory nerve cells they are supposed to stimulate. And since the position of the electrodes is limited by the anatomy of the cochlea, the alternative is to coax the neurons to grow toward the electrodes.
Neurons will grow toward certain signaling factors, among them brain-derived neurotrophic factor (BDNF). So the researchers reasoned that if they could get cells near the electrodes to express BDNF, it might serve as a beacon for auditory nerve cells to send outgrowths toward those cells.
"The cochlear neurons express receptors for the BDNF that we have made the cells close to the electrodes express," corresponding author Gary Housley, of the University of New South Wales, told BioWorld Today. "The BDNF acts as a nerve growth factor and the surviving neurons . . . [follow] the concentration gradient of the BDNF – which is towards the cochlear implant electrodes."
In their experiments, which were performed in guinea pigs, the authors used the cochlear implants to deliver pulses of electroporating current during the implantation procedure. That current enabled nearby cells to take up DNA plasmids containing BDNF, as well as a fluorescent marker. The cells expressed those genes for a few weeks – long enough to coax auditory nerve cells to send outgrowths in their direction.
The team plans, among other things, to see whether they can get gene expression to last longer than a few weeks by tweaking their procedure, though Housley noted that from other studies, there are grounds for optimism that once the nerve fibers have regenerated, the active electrical stimulation by the cochlear implant in operation will be sufficient to make them remain in touch with the electrodes.
Housley and his team then tested whether those outgrowths made it easier to stimulate the auditory nerve, and they found that the threshold of electrical current they needed to get the auditory nerve's attention was lower in treated animals. Electrical recordings suggested that they were able to transmit a greater range of signals in treated animals, which could in principle translate into a better transmission of complex sounds.
The scientists hope that specifically for cochlear implants, the approach – which they next plan to validate in a clinical trial – will help improve pitch perception. But the work also provides proof of principle that brain stimulation and gene therapy could be a more general package deal.
Deep brain stimulation is an approved treatment for tremor, Parkinson's disease and dystonia. And it is being tested in other indications, including depression.
"The directed gene delivery by close-field electroporation has advantages in that it can support a wide range of therapeutic gene cassettes – far greater with regard to size and hence design than viral packaging [for example]," Housley said. "So neurological applications can be tailored to enable a range of existing viral-based approaches that are not currently tenable due to safety constraints and issues of spread."