ohlfe001@umn.edu
Education
Dr. Ohlfest is an Assistant Professor and the Director of the gene therapy program in Department of Neurosurgery and a faculty member of the Stem Cell Institute. Dr. Ohlfest studied molecular biology as an undergraduate at Iowa State University and received his Ph.D. in molecular genetics and cell biology at the University of Minnesota. He then did post-doctoral research with Dr. Andrew Freese at the University of Minnesota focusing on gene therapy in the central nervous system.
Research Interests
Dr. Ohlfest's research interests are focused on using gene transfer to correct disease and manipulating endogenous progenitor cells by gene transfer. In addition, targeted therapies for the eradication of so called "brain tumor stem cells", the tumor cells capable of self-renewal and the cause of tumor relapse, is in an area of ongoing investigation in his lab. The mammalian brain harbors endogenous progenitor cells capable of differentiating into neurons, oligodendrocytes, and astrocytes. There are many human diseases that could theoretically benefit from genetic modification of these cells in order to reconstitute the brain with metabolically corrected cells. Specifically, diseases that result from the lack of a single enzyme are attractive targets for gene therapy. The goal of this research is to identify methods to introduce therapeutic genes into the brain-derived progenitor cells, and cause these corrected cells to expand and differentiate in sufficient numbers to treat the disease.
Malignant gliomas are fatal brain tumors that are comprised of brain tumor stem cells, and also more phenotypically mature tumor cells. The genetic heterogeneity of these tumors, and resilient stem cell-like component, makes achieving complete cures difficult with conventional therapies. The focus of this research is to develop effective gene therapies and immuno therapies to eradicate the brain tumor stem cells that are the likely cause of tumor recurrence and death. Using therapies that selectively kill these cells, or evoke an anti-tumor immune response, shows promise in improving the prognosis for glioma patients. As director of the gene therapy program in the department of neurosurgery, the development of safe and effective gene transfer methods is a top priority.
Currently both viral and nonviral gene transfer methods are being developed, each with its advantages and disadvantages. Specifically, adenovirus is being utilized to introduce cytotoxic and immuno-stimulatory genes into glioma models. Nonviral plasmid vectors, including the Sleeping Beauty transposable element and Bacteriophage C31 integrase, are being developed for their application to long-term gene transfer to treat recessive genetic disorders and select malignancies of the brain. Tumor-targeted viral and nonviral gene transfer using tumor-selective ligands is an area of active research. Novel gene delivery devices for increased distribution of gene therapy vectors are also being developed.
Specific Projects
1. Gene Transfer to Endogenous Neural Progenitor Cells:
2. Gene Therapy / Immuno Therapy for Brain Tumors:
3. Novel Gene Delivery Tools and Infusion Devices:
Publications
1. Ohlfest, J. R., P.D. Lobitz, S.G. Perkinson and D.A. Largaespada (2004). Integration and long-term expression in xenografted human glioblastoma cells using a plasmid-based transposon system. Mol Ther. : 260-268.
2. Ohlfest, J. R., Frandsen, J. L., Fritz, S., Lobitz, P. D., Perkinson, S. G., Clark, K. J., Nelsestuen, G., Key, N. S., McIvor, R. S., Hackett, P. B., and Largaespada, D. A. Phenotypic correction and long-term expression of factor VIII in hemophilic mice by immunotolerization and nonviral gene transfer using the Sleeping Beauty transposon system. Blood. 2005 Apr 1;105(7):2691-8. Epub 2004 Dec 2.
3. Wiesner S.M., Freese A.B., Ohlfest J.R. Emerging concepts in glioma biology: implications for clinical protocols and rational treatment strategies. Neurosurg Focus. 2005;19:E3.
4. Ohlfest J.R., Demorest, Z.L., Mootoka, Y., Vengco, I., Oh, S., Chen, E., Scappaticci, F.A., Saplis, R.J., Ekker, S.E., Low, W.C., Freese, A.B., and Largaespada, D.A. Combinatorial antiangiogenic gene therapy by nonviral gene transfer using the sleeping beauty transposon causes tumor regression and improves survival in mice bearing intracranial human glioblastoma. Mol Ther. 2005;12:778-788.
5. Ohlfest, J.R.,Freese, A.B., and Largaespada, D.A. Nonviral Vectors for Cancer Gene Therapy: Prospects for Integrating Vectors and Combination Therapies Current Gene Therapy. 2005; Vol 5, No. 6, December.
6. Candolfi M, Kroeger KM, Pluhar GE, Liu C, Barcia C, Bergeron J, Puntel M, Curtin JF, McNiel EA, Freese AB, Ohlfest JR, Moore PF, Kuoy W, Lowenstein PR, Castro MG. (2006) Adenoviral mediated gene transfer into the dog brain in vivo. Neurosurgery (In Press).
7. Wu A., Xiao J., Chen W., Hall W.A., Low W.C., and Ohlfest J.R. Expression of MHC I and NK ligands on human CD133+ brain tumor cells: possible targets of immunotherapy. 2006 Journal of Neuro-oncology (in press).