Timed GDNF gene therapy using an immune-evasive gene switch promotes long distance axon regeneration
Timed GDNF gene therapy using an immune-evasive gene switch promotes long distance axon regeneration
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DOI：
10.1093/brain/awy340
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发表时间：
2019-02-01
期刊：
影响因子：
14.5
通讯作者：
Verhaagen, Joost
中科院分区：
文献类型：
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作者：
Eggers, Ruben;de Winter, Fred;Verhaagen, Joost
近端神经损伤患者的神经外科修复导致功能恢复不令人满意。神经营养因子的基因治疗是促进轴突再生的有力策略。胶质细胞源性神经营养因子（GDNF）基因治疗促进运动神经元存活和轴突生长，然而，不受控制的GDNF递送导致轴突截留。我们报告说，时间限制GDNF表达（1个月）使用免疫逃避多西环素诱导的基因开关衰减局部轴突截留在撕脱再植腹侧脊神经根，足以促进长期运动神经元存活（24周），并促进复合肌肉动作电位的恢复8周。这些改善与运动轴突长距离再生的增加有关。相反，持续GDNF表达通过诱导轴突截留而损害轴突再生。这些发现表明，定时表达可以解决不受控制的生长因子递送的有害作用，并表明诱导生长因子基因治疗可以用于增强大鼠近端神经损伤的神经外科修复后轴突再生的功效。这项临床前研究是针对严重近端神经病变患者正在进行的神经营养因子基因治疗开发的重要一步。
Neurosurgical repair in patients with proximal nerve lesions results in unsatisfactory recovery of function. Gene therapy for neurotrophic factors is a powerful strategy to promote axon regeneration. Glial cell line-derived neurotrophic factor (GDNF) gene therapy promotes motor neuron survival and axon outgrowth; however, uncontrolled delivery of GDNF results in axon entrapment. We report that time-restricted GDNF expression (1 month) using an immune-evasive doxycycline-inducible gene switch attenuated local axon entrapment in avulsed reimplanted ventral spinal roots, was sufficient to promote long-term motor neuron survival (24 weeks) and facilitated the recovery of compound muscle action potentials by 8 weeks. These improvements were associated with an increase in long-distance regeneration of motor axons. In contrast, persistent GDNF expression impaired axon regeneration by inducing axon entrapment. These findings demonstrate that timed expression can resolve the deleterious effect of uncontrolled growth factor delivery and shows that inducible growth factor gene therapy can be employed to enhance the efficacy of axon regeneration after neurosurgical repair of a proximal nerve lesion in rats. This preclinical study is an important step in the ongoing development of a neurotrophic factor gene therapy for patients with severe proximal nerve lesions.