Gene Therapy for Regeneration and Preservation of Spiral Ganglion Neurons

Abstract

Spiral ganglion neurons (SGNs) are the targets for electrical stimulation from cochlear implants (CI), and SGN lesions can affect CI-mediated auditory performance. Primary diseases in SGNs are relatively rare; however, loss of hair cells, which is the most common cause of sensorineural hearing loss, usually leads to the secondary degeneration of SGNs. Therefore, most of the attempts at gene therapy for SGNs have been intended to prevent degeneration of SGNs following loss of hair cells in order to improve CI outcomes. Previous studies showed that direct administration of exogenous peptide neurotrophic factors into the cochlea enhanced the survival of SGNs after noise- or aminoglycoside-induced loss of hair cells; however, this effect was transient. Other studies demonstrated that gene therapy using viral-derived vectors, especially adenoviral and adeno-associated viral vectors, successfully achieved the long-term expression of a gene encoding neurotrophic factors and promoted SGN survival and neurite extension of SGNs in ototoxically deafened guinea pigs and congenitally deaf mice with a genetic mutation. Inoculation of viruses expressing glial cell-derived neurotrophic factor (GDNF) or brain-derived neurotrophic factor (BDNF) into the scala tympani decreased thresholds for electrically evoked auditory brainstem responses, suggesting the clinical importance of gene therapy using neurotrophic factor-expressing viruses to improve CI outcomes.