Adenovirus-Mediated Expression of Brain-Derived Neurotrophic Factor Protects Spiral Ganglion Neurons from Ototoxic Damage

Abstract

Hair cell loss, the most common cause of deafness, is often associated with auditory nerve degeneration. Our goal was to determine the influence of combined ciliary-derived neurotrophic factor (CNTF) and brain-derived neurotrophic factor (BDNF) gene therapy on the survival of spiral ganglion neurons (SGNs) after elimination of inner hair cells in the mature guinea pig ear. Seven days after bilateral deafening, a 5-µl suspension of CNTF and/or BDNF adenovirus vectors was injected into the left scala tympani through the round window. Animals were sacrificed 28 days after deafening, and their inner ears were prepared for SGN counts. The SGN counts revealed that BDNF alone and the combined CNTF and BDNF treatment significantly enhanced SGN survival. CNTF did not significantly enhance the protective effect of BDNF. These data present possible strategies for enhancing SGN survival in cochlear implant procedures.

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.…”

Progressive Deafness and Altered Cochlear Innervation in Knock-Out Mice Lacking Prosaposin

“…There is currently a concerted effort by a number of investigators to find ways to improve neuronal survival for profoundly deaf patients who are cochlear implant candidates, because improved neuronal survival would theoretically improve cochlear implant performance (Gao, 1998;Marzella and Clark, 1999;Shepherd and Hardie, 2001;Nakaizumi et al, 2004). If the molecular mechanism of afferent and efferent neuronal proliferation identified in this study can be teased apart and focally applied to the inner ear of profoundly deaf patients, it is possible that increased growth of afferent neurons could translate into improved performance with the cochlear implant.…”

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

“…Brain derived neurotrophic factor (BDNF) is a neurotrophin involved in the development and maintenance of spiral ganglion cells (Ernfors et al, 1995;Fritzsch et al, 1997;Malgrange et al, 1996;Pirvola et al, 1992). Addition of BDNF to the cochlear fluids can prevent the degeneration of spiral ganglion neurons after hair cells are lost in mature ears (Miller et al, 1997;Nakaizumi et al, 2004;Staecker et al, 1998). Various techniques of introducing BDNF into the cochlea have been used, including direct infusion into the scala tympani (Miller et al, 1997) and gene transfer using recombinant viral vectors (Nakaizumi et al, 2004;Staecker et al, 1998).…”

“…Addition of BDNF to the cochlear fluids can prevent the degeneration of spiral ganglion neurons after hair cells are lost in mature ears (Miller et al, 1997;Nakaizumi et al, 2004;Staecker et al, 1998). Various techniques of introducing BDNF into the cochlea have been used, including direct infusion into the scala tympani (Miller et al, 1997) and gene transfer using recombinant viral vectors (Nakaizumi et al, 2004;Staecker et al, 1998). Direct cochlear infusion of BDNF and other neurotrophic factors using mini-osmotic pumps allows regulation of the duration and quantity of infusion, but their use increases surgical complexity.…”