Enhanced Auditory Neuron Survival Following Cell-Based BDNF Treatment in the Deaf Guinea Pig

Abstract

Exogenous neurotrophin delivery to the deaf cochlea can prevent deafness-induced auditory neuron degeneration, however, we have previously reported that these survival effects are rapidly lost if the treatment stops. In addition, there are concerns that current experimental techniques are not safe enough to be used clinically. Therefore, for such treatments to be clinically transferable, methods of neurotrophin treatment that are safe, biocompatible and can support long-term auditory neuron survival are necessary. Cell transplantation and gene transfer, combined with encapsulation technologies, have the potential to address these issues. This study investigated the survival-promoting effects of encapsulated BDNF over-expressing Schwann cells on auditory neurons in the deaf guinea pig. In comparison to control (empty) capsules, there was significantly greater auditory neuron survival following the cell-based BDNF treatment. Concurrent use of a cochlear implant is expected to result in even greater auditory neuron survival, and provide a clinically relevant method to support auditory neuron survival that may lead to improved speech perception and language outcomes for cochlear implant patients.

Lack of Brain-Derived Neurotrophic Factor Hampers Inner Hair Cell Synapse Physiology, But Protects against Noise-Induced Hearing Loss

“…Accordingly, a gradual age-related loss of BDNF in the cochlea, as previously shown to occur in the third life span in rats and gerbils , or altered BDNF levels in psychiatric and neurodegenerative disorders (Lu and Martinowich, 2008;Krishnan and Nestler, 2010;Pardon, 2010), may be discussed in the context of altered loudness perception that has been described in these diseases (Frisina, 2009;Aznar and Knudsen, 2011). Finally, the current ideas to propose BDNF as a promising future therapeutic for hearing deficits (Pettingill et al, 2011) may be revisited in the context of the present study.…”

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

“…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. Without a doubt, osmotic minipump, gene therapy, stem cell therapy, and cochleostomy are hopeful steps toward successful treatment of the degeneration of SGCs in the inner ear and the loss of hearing.…”

“…Schwann cells, which are capable of expressing BDNF, have been effectively transplanted into the subretinal space of RCS rat strains 105 and to the guinea pig's cochlea. 182 However, viral vector and cell-based therapy are still limited by surgical technique and human immune system. As a promising solution to protect cells from rejection and tumorigenicity, cell transplantation and gene transfer, combined with encapsulation technologies, has been suggested.…”

“…As a promising solution to protect cells from rejection and tumorigenicity, cell transplantation and gene transfer, combined with encapsulation technologies, has been suggested. 182 BDNF-expressing Schwann cells with alginate encapsulation technology have been applied to deaf guinea pigs and this showed survival effect on auditory neurons. Although BDNF has not been used with such strategy for the treatment of posterior eye segment, data about a Phase I clinical trial exploiting immortalized human retinal pigmented epithelial cells overexpressing CNTF for the treatment of retinitis pigmentosa have been published.…”

Combining Cell-Based Therapies and Neural Prostheses to Promote Neural Survival

“…Consequently, the promise of NT therapy to rescue SGNs after SNHL has yet to be realized, and effective and safe drug administration strategies for application in the inner ear remains elusive. The use of cell-based therapies provides a clinically viable NT delivery technique that is less susceptible to adverse side effects than pump-based delivery methods [21][22][23]. In the present study, choroid plexus cells (NTCells, Living Cell Technologies, Auckland, New Zealand), which produce and release a cocktail of NTs [24], were encapsulated in biocompatible alginate and implanted into the neonataldeafened cat cochlea in combination with a cochlear implant electrode array.…”