THER-04. OLFACTORY ENSHEATHING CELLS TRAVEL THEIR NATURE ROUTE FROM NASAL CAVITY TO CNS AND DELIVER THERAPEUTIC TRANSGENES TO HIGH-GRADE PEDIATRIC GLIOMAS

摘要

The olfactory ensheathing cells (OECs) are a unique glial cell type playing a role in promoting the axonal growth of neuronal receptors from the nasal mucosa towards the olfactory bulb during physiological turnover. OECs have the ability to migrate from the peripheral nervous system to the central nervous system, which is critical for the development of the olfactory system. Owing to their ability to guide axonal outgrowth, interact with astrocytes, and their immuno-modulatory and phagocytic properties, OECs showed promising results in regenerative medicine, including spinal cord injury and amyotrophic lateral sclerosis in the clinic, but were never studied in the context of cancer. Here, we evaluated for the first time OEC potential for pediatric gliblastoma gene therapy. We extracted/cultured OECs from mice olfactory bulb and established their phenotype by immunofluorescence microscopy. We first confirmed OEC tropism to intracranial glioblastoma, both at the primary tumor and the infiltrating single stem-like cells and showed that two cytokines, TNFα and IL-6, are responsible for this tropism. We chose the intranasal delivery since this route will bypass the blood-brain barrier, limit systemic side effects, and is the natural migration path of OECs to CNS. We then evaluated the potential of OEC as a delivery vehicle for pediatric glioma gene therapy by genetically engineering these cells to express cytosine deaminase (CD) under the control of CMV promoter. Mice bearing intracranial glioblastoma tumors injected intranasally with OEC-CD and treated with 5-FC showed slower tumor growth and increase in survival compared to controls. Our findings show for the first time OECs tropism to pediatric glioma tumors and their potential for brain cancer gene therapy using intranasal delivery. OECs have the advantage over other typical stem cells in that they can be easily obtained from olfactory bulb, allowing autologous transplantation and overcoming ethical issues.