ERANET 1 NEURON 2:Tools for long-lasting and safe CNS gene transfer

中枢神经系统（CNS）对基因治疗提出了特定的挑战。在这里，我们将提供解决方案，以应对这些特定的挑战，并克服现有的风险与基因调控试剂的交付。其主要目的是开发用于在CNS中诱导长寿命、安全、细胞类型特异性和受调控的转基因表达的工具，以应用于神经退行性疾病的治疗。整合酶缺陷型非整合慢病毒载体将用于基因转移。通过对流增强递送（CED）与神经元特异性启动子的组合将实现广泛但细胞类型特异性的靶向表达分布。将可调控的表达系统扩增到基于非整合附加型的载体中将允许根据治疗要求调节表达，并且因此将进一步增强治疗安全性。与子项目2和3一起，这些工具将用于靶向神经元细胞周期激活的关键分子开关，以预防或减缓神经退行性变。基因治疗工具的模块化特征将允许在替代规范中适应该概念，用于治疗需要神经元特异性靶向的其他神经系统疾病。

The central nervous system (CNS) poses specific challenges to gene therapy. Here we will provide solutions to meet these specific challenges and overcome existing risks with delivery of reagents for gene regulation. It is the principal aim to develop tools to induce long-lived, safe, cell-type specific and regulated transgene expression in the CNS for application in therapy of neurodegenerative disorders. Integrase-deficient non-integrating lentiviral vectors will be used for gene transfer. Widespread but cell-type-specific targeted distribution of expression will be achieved through combination of convection enhanced delivery (CED) with neuron-specific promoters. Incorporating regulatable expression systems into non-integrating episomal based vectors will allow for tuning expression according to therapeutic requirements and will, thus, further enhance therapeutic safety. Together with subprojects 2 and 3, these tools will be used to target critical molecular switches of cell cycle activation in neurons to prevent or slow down neurodegenera-tion. The modular character of the gene therapeutic tools will allow to adapt the concept in alter-native specifications for the treatment of other neurological disorders which require neuron-specific targeting.