The management of malignant gliomas remains one of the most challenging issues in neuroscience. Gene therapy strategies currently used in clinical trials employ viral vectors to deliver therapeutic transgenes directly to normal and tumor cells within the central nervous system. Viral vectors, however, have a number of theoretical and practical limitations. Embryonic stem cells (ESC) are totipotent cells with unlimited proliferative capacity, and, unlike other cell types, can be permanently and precisely genetically modified without the use of viral vectors. We have published a protocol for generating highly pure populations of transgenic astrocytes from mouse ESC, while minimizing contamination by undifferentiated ES cells. We have demonstrated that we can generate a pure population of transgenic ESC-derived astrocytes with a highly regulated, robust tetracycline-inducible expression of transgenes. We have demonstrated that ESC-derived astrocytes conditionally expressing pro-apoptotic genes induce apoptosis in vitro and in vivo in malignant glioma cells. Finally, we have shown that ESC-derived astrocytes conditionally expressing transgenes have migratory capacities in vitro and in vivo. Recent data show that the melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL- 24) gene induces apoptosis in a variety of tumor cell lines, including gliomas, while sparing normal cells. We have engineered ESC-derived astrocytes to conditionally express mda-7/IL-24. It is our hypothesis that ESC-derived astrocytes expressing mda-7/IL-24 may represent an effective and novel approach for treatment of human malignant gliomas. In this proposal, we will test our hypothesis in the following specific aims. 1) To determine the behavior of mouse ESC-derived astrocytes conditionally expressing mda-7/IL-24 in situ after grafting into the mouse brain;2) To determine the pro-apoptotic effects of ESC-derived astrocytes conditionally expressing mda-7/IL-24 in vitro, in vivo, and in situ on human malignant glioma;3) To investigate the effects of transgenic mda-7/IL-24 to enhance prop-apoptotic effects of conventional ionizing radiation (IR) and those of transgenic TRAIL. The effective treatment of malignant gliomas will depend on the development of therapeutic strategies that can eradicate residual tumor cells left behind after sophisticated surgical resection or stereotactically delivered high dose radiation. Therefore, the migratory characteristic of ESC-derived astrocytes combined with the capability of carrying transgenes tightly regulated by external control, makes ESC-mediated gene delivery a promising new treatment modality for human malignant gliomas.

Public Health Relevance

The management of malignant gliomas remains one of the most challenging issues in neuroscience. Gene therapy strategies currently used in clinical trials. Embryonic stem cells (ESCs) are totipotent cells with unlimited proliferative capacity has the potential of using as a vector for gene therapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA129489-05
Application #
8269964
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Arya, Suresh
Project Start
2008-08-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2014-05-31
Support Year
5
Fiscal Year
2012
Total Cost
$341,162
Indirect Cost
$139,887
Name
Icahn School of Medicine at Mount Sinai
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
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Germano, Isabelle M; Binello, Emanuela (2014) Stem cells and gliomas: past, present, and future. J Neurooncol 119:547-55
Binello, Emanuela; Germano, Isabelle M (2012) Stem cells as therapeutic vehicles for the treatment of high-grade gliomas. Neuro Oncol 14:256-65
Binello, Emanuela; Germano, Isabelle M (2011) Targeting glioma stem cells: a novel framework for brain tumors. Cancer Sci 102:1958-66
Germano, I M; Emdad, L; Qadeer, Z A et al. (2010) Embryonic stem cell (ESC)-mediated transgene delivery induces growth suppression, apoptosis and radiosensitization, and overcomes temozolomide resistance in malignant gliomas. Cancer Gene Ther 17:664-74
Germano, Isabelle; Swiss, Victoria; Casaccia, Patrizia (2010) Primary brain tumors, neural stem cell, and brain tumor cancer cells: where is the link? Neuropharmacology 58:903-10