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

• Applicants: Dr. Franz-Josef Müller; Professor Dr. Nils Ole Schmidt
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Clinical Neurology; Neurosurgery and Neuroradiology
• Term: from 2014 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 253853162

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

• DFG Programme: Research Grants