Embryonic stem cell–derived astrocytes: a novel gene therapy vector for brain tumors

Abstract

Object For gene therapy strategies currently in clinical trials, viral vectors are used to deliver transgenes directly to normal and tumor cells within the central nervous system (CNS). The use of viral vectors is limited by several factors. The aim of this study was to assess whether embryonic stem cell (ESC)–derived astrocytes expressing a doxycycline-inducible transgene can be used as a vector for gene therapy. Methods The authors generated a pure population of ESC-derived astrocytes carrying a transgene, tumor necrosis factor–related apoptosis-inducing ligand (TRAIL), inserted in the chromosome under the control of a highly regulated doxycycline-inducible expression system. Fully differentiated ESC-derived astrocytes were stereotactically transplanted in the mouse brain, and then cell migration and transgene expression were studied. Results The ESC-derived astrocytes started to migrate from the transplant site 48 hours after the procedure. They were found to have migrated throughout the brain tissue by 6 weeks. Transplanted ESC-derived astrocytes expressed the TRAIL transgene after doxycycline induction throughout the duration of the experiment. Teratoma formation was not observed in long-term experiments (12 weeks). Conclusions These data show that ESC-derived astrocytes can be used as delivery vectors for CNS tumors. This technique might have a major impact on the treatment of patients with malignant gliomas and a wide spectrum of other neurological diseases.