Exploring the therapeutic potential of induced neural stem cells for Parkinson disease treatment employing a syngenic monkey model

• Applicant: Professor Dr. Frank Edenhofer
• Subject Area: Experimental Models for the Understanding of Nervous System Diseases ; Molecular Biology and Physiology of Neurons and Glial Cells ; Cell Biology
• Term: from 2015 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 266317206

Parkinson disease (PD) is a degenerative disorder of the human central nervous system, which affects mostly dopamine-generating cells in the substantia nigra. Although treatments have been developed to target symptoms of PD, no clinically approved therapy is available. Cell replacement therapy holds great promise for treatment of PD and has successfully been used in animal models. A major roadblock for widespread clinical application represents the source of transplantable cells though. Cells from fetal brain tissue as well as embryonic stem cells (ESCs) have been harnessed. However, the use of those cells raises major ethical considerations and involves a tumorigenic potential, respectively. Moreover, cells used for cell replacement therapy ideally should be patient-specific to minimize immune rejection of transplants. Recent developments in cellular reprogramming provide new opportunities for autologous cell replacement therapy. Fibroblasts can be converted into induced pluripotent stem cells (iPSCs) by overexpression of four transcription factors. iPSCs are functionally equivalent to ESCs and can thus be differentiated into any desired cell type. In several animal models, e.g. for PD, iPSCs could be applied for successful cell replacement therapy. However, since iPSC-derived differentiated cells might still contain residual undifferentiated stem cells, there is a high risk of tumor formation after cell replacement therapy using iPSC derivatives. Additionally, reprogramming somatic cells to pluripotency and differentiating them subsequently into the desired cell type is a time-consuming and costly process. Recently, we identified an alternative reprogramming pathway by directly converting somatic cells into multipotent neural stem cells, thereby circumventing the pluripotent state and thus limiting the tumorigenic risk. Murine fibroblasts were reprogrammed into proliferating induced neural stem cells (iNSCs), which can be differentiated into neurons, astrocytes and oligodendrocytes. We showed the functionality of murine iNSCs in small animal models, however, the therapeutic potential of primate iNSCs in more adequate models, like the monkey remains unexplored. Here we propose to apply iNSC reprogramming technology to establish human and monkey iNSCs and test their applicability for cell therapy in large animal models. The conversion should be achieved from fibroblasts as well as mesenchymal stem cells by the overexpression of transcription factors, either by conventional lentiviral transduction or transgene-free methods. Dopaminergic neurons will be generated from the iNSCs and after characterization and validation their therapeutic potential will be tested by transplantation in an autologous MPTP-monkey model as well as in a 6-OHDA mouse model. We expect this project to provide proof-of-principle data of a novel autologous cell transplantation paradigm for the therapeutic treatment of Parkinson's disease.

• DFG Programme: Research Grants
• International Connection: Austria, China
• Cooperation Partner: Professor Dr. Zhiguo Chen