Cochlear implants and ex vivo BDNF gene therapy protect spiral ganglion neurons

Abstract

Spiral ganglion neurons often degenerate in the deaf ear, compromising the function of cochlear implants. Cochlear implant function can be improved by good preservation of the spiral ganglion neurons, which are the target of electrical stimulation by the implant. Brain derived neurotrophic factor (BDNF) has previously been shown to enhance spiral ganglion survival in experimentally deafened ears. Providing enhanced levels of BDNF in human ears may be accomplished by one of several different methods. The goal of these experiments was to test a modified design of the cochlear implant electrode that includes a coating of fibroblast cells transduced by a viral vector with a BDNF gene insert. To accomplish this type of ex vivo gene transfer, we transduced guinea pig fibroblasts with an adenovirus with a BDNF gene cassette insert, and determined that these cells secreted BDNF. We then attached BDNF-secreting cells to the cochlear implant electrode via an agarose gel, and implanted the electrode in the scala tympani. We determined that the BDNF expressing electrodes were able to preserve significantly more spiral ganglion neurons in the basal turns of the cochlea after 48 days of implantation when compared to control electrodes. This protective effect decreased in the higher cochlear turns. The data demonstrate the feasibility of combining cochlear implant therapy with ex vivo gene transfer for enhancing spiral ganglion neuron survival.

Effects of Brain-Derived Neurotrophic Factor (BDNF) and Electrical Stimulation on Survival and Function of Cochlear Spiral Ganglion Neurons in Deafened, Developing Cats

“…However, the use of osmotic pumps to deliver neurotrophic factors clearly is not a good option for clinical application, particularly due to concerns about infection Staecker et al 2010). Numerous recent studies have explored alternative strategies for cochlear delivery of neurotrophins (Hendricks et al 2008;Richardson et al 2008), including cell-based therapies (Warnecke et al 2007;Pettingill et al 2008;Wise et al 2011), hydrogels (Endo et al 2005, and gene therapy using adenovirus-mediated expression of neurotrophic factors (Nakaizumi et al 2004;Rejali et al 2007;Chikar et al 2008;Wise et al 2010). These methods may provide better alternatives in the future, but they are still under development and concerns about potential side effects and risks have not yet been adequately addressed.…”

Targeted delivery of brain-derived neurotrophic factor for the treatment of blindness and deafness

“…Then, the electrode with encased BDNF was transplanted into the scala tympani in a hydrogel scaffold on a CI to increase the survival of SGCs. 171 Another study that combined cell-based gene transfer with alginate technology, had demonstrated the survival effects on auditory neurons of encapsulated BDNF-expressing Schwann cells. 182 Such transplanted cells, encapsulated in a biocompatible matrix, would be protected against strong immune responses, and this would allow the patients to avoid using toxic immunodepressants, thus minimizing the associated risk of transplant rejection.…”

Cochlear implants: A remarkable past and a brilliant future

“…One possibility for providing a close apposition is to promote the growth of neurites from the ganglion cells toward the electrodes in the ST with controlled delivery of neurotrophic drugs into the perilymph (Roehm and Hansen, 2005;Pettingill et al, 2007;Rejali et al, 2007;Vieira et al, 2007;Hendricks et al, this issue). Such growth would bring the target to the electrodes.…”