Intrathecal injection of HVJ‐E containing HGF gene to cerebrospinal fluid can prevent and ameliorate hearing impairment in rats
Intrathecal injection of HVJ‐E containing HGF gene to cerebrospinal fluid can prevent and ameliorate hearing impairment in rats
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DOI：
10.1096/fj.03-0567fje
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发表时间：
2004-01
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通讯作者：
Kazuo Oshima;M. Shimamura;S. Mizuno;K. Tamai;K. Doi;R. Morishita;Toshikazu Nakamura;T. Kubo;Y. Kaneda
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文献类型：
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作者：
Kazuo Oshima;M. Shimamura;S. Mizuno;K. Tamai;K. Doi;R. Morishita;Toshikazu Nakamura;T. Kubo;Y. Kaneda
听力障碍是人类最常见的感觉障碍，需要在治疗技术上取得突破。一种技术是使用载体系统到达内耳，另一种是通过治疗分子。在这里，我们开发了一种新的基因治疗策略，将肝细胞生长因子(HGF)与日本包膜血凝病毒(HVJ-E)载体相结合。将含人HGF基因的hVJ-E经大鼠枕大池注入脑脊液后到达内耳区，并在内耳的螺旋神经节细胞(SGCs)中检测到人HGF基因的表达。人HGF还可诱导SGCs内源性HGF及其受体c-Met的表达。卡那霉素可通过诱导毛细胞变性和神经节细胞凋亡而导致大鼠听力损伤。通过在卡那霉素治疗前进行HGF基因转移，既能防止HSC丢失，又能防止SGCs的凋亡。此外，听觉脑干反应评估的听力功能维持在正常水平。在卡那霉素治疗2wk后进行HGF基因转移，听力障碍明显恢复。这些结果为治疗感音神经性听力障碍提供了一种新的有效的治疗策略。
Hearing impairment, which is the most prevalent sensory deficit of human beings, needs a breakthrough in therapeutic technologies. One technology is the usage of a vector system to reach the inner ear, and another is by a therapeutic molecule. Here we developed a novel gene therapy strategy by combining hepatocyte growth factor (HGF) with hemagglutinating virus of Japan envelope (HVJ‐E) vector. When HVJ‐E containing human HGF gene was injected intrathecally into the cerebrospinal fluid via cisterna magna of rats, the vector reached the inner ear region, and human HGF gene expression was detected in the spiral ganglion cells (SGCs) of the inner ear. Expression of endogenous rat HGF and its receptor, c‐Met, was also induced in SGCs by human HGF. Kanamycin treatment results in hearing impairment by inducing degeneration of hair cells (HCs) and apoptosis of SGCs in rats. By HGF gene transfer before kanamycin treatment, both loss of HCs and apoptosis of SGCs were prevented. Furthermore, hearing function, evaluated by auditory brainstem response, was maintained at a normal level. When HGF gene transfer was performed 2 wk after kanamycin treatment, hearing impairment was significantly recovered. These results indicate a novel and effective therapeutic strategy against sensorineural hearing impairment.