St Peter Madeleine, Brough Douglas E, Lawrence Anna, Nelson-Brantley Jennifer, Huang Peixin, Harre Jennifer, Warnecke Athanasia, Staecker Hinrich
University of Kansas School of Medicine, Kansas City, KS, United States.
Precigen Inc., Gaithersburg, MD, United States.
Front Bioeng Biotechnol. 2022 Jun 3;10:892969. doi: 10.3389/fbioe.2022.892969. eCollection 2022.
Survival and integrity of the spiral ganglion is vital for hearing in background noise and for optimal functioning of cochlear implants. Numerous studies have demonstrated that supplementation of supraphysiologic levels of the neurotrophins BDNF and NT-3 by pumps or gene therapy strategies supports spiral ganglion survival. The endogenous physiological levels of growth factors within the inner ear, although difficult to determine, are likely extremely low within the normal inner ear. Thus, novel approaches for the long-term low-level delivery of neurotrophins may be advantageous. This study aimed to evaluate the long-term effects of gene therapy-based low-level neurotrophin supplementation on spiral ganglion survival. Using an adenovirus serotype 28-derived adenovector delivery system, the herpes latency promoter, a weak, long expressing promoter system, has been used to deliver the BDNF or NTF3 genes to the inner ear after neomycin-induced ototoxic injury in mice. Treatment of the adult mouse inner ear with neomycin resulted in acute and chronic changes in endogenous neurotrophic factor gene expression and led to a degeneration of spiral ganglion cells. Increased survival of spiral ganglion cells after adenoviral delivery of BDNF or NTF3 to the inner ear was observed. Expression of BDNF and NT-3 could be demonstrated in the damaged organ of Corti after gene delivery. Hearing loss due to overexpression of neurotrophins in the normal hearing ear was avoided when using this novel vector-promoter combination. Combining supporting cell-specific gene delivery via the adenovirus serotype 28 vector with a low-strength long expressing promoter potentially can provide long-term neurotrophin delivery to the damaged inner ear.
螺旋神经节的存活和完整性对于在背景噪声中听力以及人工耳蜗的最佳功能至关重要。大量研究表明，通过泵或基因治疗策略补充超生理水平的神经营养因子BDNF和NT-3可支持螺旋神经节的存活。内耳内生长因子的内源性生理水平虽然难以确定，但在正常内耳中可能极低。因此，神经营养因子长期低水平递送的新方法可能具有优势。本研究旨在评估基于基因治疗的低水平神经营养因子补充对螺旋神经节存活的长期影响。使用源自腺病毒血清型28的腺载体递送系统，疱疹潜伏启动子，一种弱的、长期表达的启动子系统，已被用于在新霉素诱导的小鼠耳毒性损伤后将BDNF或NTF3基因递送至内耳。用新霉素治疗成年小鼠内耳导致内源性神经营养因子基因表达的急性和慢性变化，并导致螺旋神经节细胞变性。观察到将BDNF或NTF3腺病毒递送至内耳后螺旋神经节细胞的存活率增加。基因递送后，在受损的柯蒂氏器中可证明BDNF和NT-3的表达。当使用这种新型载体 - 启动子组合时，可避免正常听力耳中神经营养因子过度表达导致的听力损失。将通过腺病毒血清型28载体进行的支持细胞特异性基因递送与低强度长期表达启动子相结合，有可能为受损内耳提供长期的神经营养因子递送。
