Preclinical development of an autologous stem-cell based gene therapy for the treatment of malignant brain tumors

神经干/祖细胞(NSC)具有固有的致病特性，可用于靶向向中枢神经系统的侵袭性恶性肿瘤输送治疗基因。在不断走向临床实现的同时，必须解决诸如干细胞系的类型和来源及其治疗应用方法等基本问题。目前，大多数干细胞系来自胚胎或胎儿组织，这引发了免疫学以及重大的后勤和伦理问题。一个理想的选择是使用能够在体外快速扩增和转基因操作的自体细胞源，然后将其重新应用于基于运动性干细胞的脑肿瘤治疗，以便靶向常规治疗后残留的浸润性肿瘤细胞。因此，我们计划从患者特异性的诱导多能干细胞(IPSC)中建立神经干细胞制剂(IPSC-NSC)，这将在临床前胶质母细胞瘤模型中进行评估。我们将专注于实施稳健且可能符合GMP的IPSC和IPSC-NSC派生方法，并将采用我们之前开发的全基因组干细胞质量控制工具(PluriTest)。基于建立的各种体外和体内模型，将评估使用HSV1-胸苷激酶/更昔洛韦系统的转基因IPSC-NSC的迁移、肿瘤归巢和治疗效率。该项目旨在通过使用患者来源的IPSC作为肿瘤靶向IPSC-NSC的细胞源来评估基于自体干细胞的脑肿瘤治疗的概念

Neural stem/progenitor cells (NSC) display inherent pathotropic properties that can be exploited for targeted delivery of therapeutic genes to invasive malignancies in the central nervous system. While advancing continuously towards clinical realization it is mandatory to address fundamental issues such as the type and origin of stem cell lines and their method of therapeutic application. Currently most stem cell lines are derived from embryonic or fetal tissue, which has raised immunological and major logistical and ethical concerns. An ideal option would be the use of an autologous cell source amenable to rapid expansion and transgenic manipulation ex vivo, which then would be reapplied as a motile stem cell-based brain tumor therapy in order to target the residual infiltrated tumor cells after conventional treatment. Therefore, we plan to establish NSC-preparations (iPSC-NSC) from patient-specific, induced pluripotent stem cells (iPSC) which will be assessed in preclinical glioblastoma models. We will focus on implementing robust and potentially GMP-compliant iPSC and iPSC-NSC derivation methods and are going to adapt genome wide stem cell quality control tools (PluriTest) previously developed by us. Based on various established in vitro and in vivo models the migration, tumor homing and therapeutic efficiency of genetically-modified iPSC-NSC using the HSV1-thymidinkinase/ganciclovir-system will be assessed. This project aims to evaluate the concept of an autologous stem cell-based brain tumor therapy by using patient derived iPSC as a cell source for tumor-targeting iPSC-NSC