Pradat P-F, Kennel P, Naimi-Sadaoui S, Finiels F, Scherman D, Orsini C, Delaere P, Mallet J, Revah F
Laboratoire de Génétique Moléculaire de la Neurotransmission et des Processus Neurodégénératifs (LGN), UMR C9923, Centre National de la Recherche Scientifique, Hôpital de la Pitié-Salpétrière, Paris, France.
Gene Ther. 2002 Oct;9(19):1333-7. doi: 10.1038/sj.gt.3301801.
Sensory neuropathies are a frequent and dose-limiting complication resulting from treatment with cisplatin. Neurotrophin-3 (NT-3) promotes the survival of the large fiber sensory neurones that are impaired in cisplatin-induced neuropathy, and may therefore serve as a preventive agent. However, the short half-life of recombinant NT-3 after systemic administration limits its clinical applications. We compared two muscle-based gene transfer strategies for the continuous delivery of NT-3 to the bloodstream in an experimental model of cisplatin-induced neuropathy. Electrophysiological studies showed that the intramuscular injection of an adenovirus encoding NT-3 partially prevented the cisplatin-induced increase in sensory distal latencies. Similar effects were observed in cisplatin-treated mice that received intramuscular injections of a plasmid encoding NT-3 associated with in vivo electroporation. The two techniques were well tolerated and induced only slight muscle toxicity. Measurement of renal function, weight and survival showed that neither technique increased the toxicity of cisplatin. Our study shows that gene therapy, using either a viral or a non-viral vector, is a promising strategy for the prevention of cisplatin-induced neuropathy.
感觉神经病变是顺铂治疗引起的常见且剂量限制性并发症。神经营养因子-3（NT-3）可促进在顺铂诱导的神经病变中受损的大纤维感觉神经元的存活，因此可能用作预防剂。然而，全身给药后重组NT-3的半衰期较短，限制了其临床应用。在顺铂诱导的神经病变实验模型中，我们比较了两种基于肌肉的基因转移策略，用于将NT-3持续递送至血流。电生理研究表明，肌肉注射编码NT-3的腺病毒可部分预防顺铂诱导的感觉远端潜伏期延长。在接受肌肉注射编码NT-3并进行体内电穿孔的质粒的顺铂治疗小鼠中也观察到了类似的效果。这两种技术耐受性良好，仅引起轻微的肌肉毒性。肾功能、体重和存活率的测量表明，这两种技术均未增加顺铂的毒性。我们的研究表明，使用病毒或非病毒载体的基因治疗是预防顺铂诱导的神经病变的一种有前景的策略。
