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殊的挑战。在这里，我们将提供解决方案，以应对这些特定的挑战，并克服基因调控试剂交付的现有风险。其主要目的是开发工具，以诱导长寿命，安全，细胞类型特异性和调节转基因表达在中枢神经系统应用于治疗神经退行性疾病。整合酶缺失的非整合慢病毒载体将用于基因转移。通过结合对流增强传递（CED）和神经元特异性启动子，可以实现广泛但细胞类型特异性的靶向表达分布。将可调节的表达系统整合到非整合的episomal载体中，将允许根据治疗要求调整表达，从而进一步提高治疗安全性。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，以防止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其他需要神经元特异性靶向治疗的神经系统疾病的替代规范中适应这一概念。

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.