Projects and Grants

The laboratory focuses on translational research for brain tumors and the study of gene therapy for malignant brain tumors. In addition, a multi-disciplinary study is focused on evaluating stem cells for therapy of brain tumors.

Current Grants

1R01 CA- NIH/NCI
PI: Isabelle Germano, M.D.

Transgenic in vivo delivery of mda-7/Il-24 for malignant glioma therapy

The management of malignant gliomas remains one of the most challenging issues in neuroscience. Gene therapy strategies currently in clinical trials use 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 recently 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 capacity in vitro and in vivo. Recent data shows 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 ES-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 conditionally expressing mda-7/IL-24 astrocytes invitro, in vivo, and in situ after transplantation in the mouse brain. 2) To determine the effects of ESC-derived, conditionally expressing mda-7/IL-24 astrocytes implanted in mice harboring tumors. 3) To investigate the effects of mda-7/IL-24 combined with conventional chemotherapy and gamma radiation for treatment of malignant brain tumor cells resistant to conventional therapy. 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 characteristics 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.

Industry

Unrestricted Educational Grant

Image Guided Neurosurgery
Computer-assisted image-guided neurosurgery is endorsed by an increasing number of neurosurgeons each year. These techniques have shown to make neurosurgery procedures more efficient, less invasive and ultimately have better clinical results. As the field of computer-science constantly advances, refinements of existing technologies and development of new are necessary. Our team collaborates with Industry to pursue these goals.

Philanthropy: Research Donations
Our grateful patients donate money to our laboratory to support ongoing pilot research studies. This support is very important as preliminary data is very important to file a major research proposal. All our experiments are focused on developing strategies to kill mailignant brain tumor cells.

Past Grants

Goldhirsh Brain Tumor Foundation
7/2007-6/2008
"Transgenic embryonic stem cell gene delivery for malignant glioma therapy"

R01 CA- NIH/NCI
7/01-6/04
"Telomerase-specific caspase transfer for gliomas"

R03-NIH/NCI
9/99 – 9/01
"Gene therapy for recurrent malignant gliomas"

RO1-NIH/NCI
7/02-6/07
"Treatment of brain tumors with 2-5A-anti-telomerase RNA"

American Brain Tumor Association
7/2006-62007
"Embryonic Stem Cells as vectors for gene delivery in brain tumors"

FDA-Orphan Product Division
10/1997-9/1999
"Deep brain stimulation for intractable dystonia"

Epilepsy Foundation of America
7/1995 - 12/1996
"Developmental aspects of the effects of hyperthermia and ihypoxia on seizures in the presence of focal hippocampal damage"

Epilepsy Foundation of America
6/1995 - 6/1996
"The effects of hyperthermia and hypoxia on seizures in the presence of focal hippocampal damage"

Epilepsy Foundation of America
7/93 - 6/94
"The role of pre-existing hippocampal injury on seizure susceptibility"

The New York Academy of Medicine
7/94-6/95
Elsberg Research GRANT
"The role of fibroblastic growth factor on the growth of primary brain tumors"

The Women's Medical Association of NYC
Mary Putnam Jacobi Fellowship
"The role of fibroblastic grown fact on astrocytes"

Congress of Neurological Surgeons
1/93-6/93
Research Fellowship
"Electrophysiological study of in vitro slices of human brain"

Dean's Research Incentive
Icahn School of Medicine
Neuronal migration disorders and epilepsy

Miles Laboratories
"Calcium channel blockers in focal cerebral ischemia"

Society of Magnetic Research in Medicine
"MR spectroscopy and imaging in cerebral ischemia"

Italian Society for Research Against Cancer
PI: Isabella Germano, M.D.
"Immunohistochemistry of childhood brain tumors"