BASIC RESEARCHES ON GENE TRANSFER FOR THE PROPHYLAXIS OF ACOUSTIC TRAUMA

有大量证据表明，耳蜗毛细胞首先受到声损伤，然后继发性耳蜗神经变性。神经源性神经营养因子（GDNF）是一种神经胶质源性神经营养因子，具有保护或预防听觉损伤的作用。另一方面，基因治疗是一项强大的技术，可用于治疗内耳疾病，包括听觉创伤。几项研究表明，利用病毒载体成功地转导了内耳细胞。在我们的第一个实验中，研究了腺病毒载体在Shaker-2小鼠耳蜗和前庭的感染。在毛细胞和支持细胞中发现腺病毒载体。在同型、异型和野生型中表达量无显著差异。毛细胞中的表达从P1下降到P5。在实验二中，我们用豚鼠研究了转移的GDNF在耳蜗中的分布模式。结果表明，GDNF在螺旋神经节细胞中表达。对侧耳蜗不表达GDNF。GDNF移植后5周，与对照组相比，螺旋神经节细胞存活率超过150 ~ 200%，差异有统计学意义。由此可见，基因转染诱导GDNF的表达对螺旋神经节细胞变性具有保护或预防作用。

There are considerable evidences suggesting that cochlear hair cells are first damaged by acoustic trauma followed by secondary degeneration of the cochlear nerve. GDNF, a glial derived neurotrophic factor, has been known to exert a protective or prophylactic role against acoustic trauma. On the other hand, gene therapy is a powerful technology that may be applied for treating inner ear disease including acoustic trauma. Several studies have shown successful transduction of inner ear cells using viral vectors. In our first experiment, an infection of adenovirus vector was studied in the Shaker-2 mouse cochleae and vestibules. Adenovirus vector was found in the hair cells and supporting cells. There was no significant difference in the expression among the homo-, hetero- and wild types. The expression in the hair cells decreased from P1 to P5. In the second experiment, we investigated the distribution pattern of transferred GDNF in the cochlea using guinea pigs. As a result, GDNF was expressed in the spiral ganglion cells. GDNF was not expressed in the contra-lateral cochlea. In 5 weeks after the transfer of GDNF, more than 150〜200% of the spiral ganglion cells were survived compare to the control, which showed a statistically significant difference. Based upon these results we can conclude that the expression of GDNF induced by gene transfer has a role on protection or prophylaxis against the degeneration of spiral ganglion cells.