Malignant glioma is the most aggressive primary brain tumor with dismal prognosis, characterized by diffuse infiltration into the normal brain parenchyma. Over the past 40 years, little improvement in survival has been achieved with multimodality therapy. Invasive glioma stem cells (GSCs) are thought to be an underlying cause of therapeutic resistance and tumor recurrence. Therefore, development of new therapeutic modalities is urgently needed. We demonstrated that human induced pluripotent stem cells (iPSCs)-derived neural stem cells (NSCs) possess a high tumor-tropic migratory capacity in the brain. Then, we established the concept of suicide gene therapy using iPSCs-derived NSCs as a cellular delivery vehicle for the treatment of malignant glioma. Lentiviral vectors integrated randomly into the host genome, raising concerns about insertional mutagenesis, oncogene activation, and transgene silencing. In order to improve the safety and to achieve the stable transgene expression, suicide gene (yCD-UPRT) was inserted in iPSCs using CRISPR/Cas9-mediated genome editing, resulting in a strong anti-tumor effect for human glioma and glioma stem xenograft mice than temozolomide (standard chemotherapy). In this research proposal, the most appropriate insertion locus of yCD-UPRT is decided via a new genome editing technology. Then, NSCs derived from clinical grade human iPSCs with yCD-UPRT are established and the quality, safety and efficacy are evaluated to obtain preclinical proof of concept.
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