Grant D. Trobridge, Ph.D.
Ph.D. in microbiology, Oregon State University
- PHARMSCI 581: Stem Cell Biology and Therapeutics
- PHARMDSCI 515: Immunology
- PHARMSCI 572: Fundamentals of Oncology
- Foamy vectors for hematopoietic stem cell gene therapy
- Cancer research
- Vector-mediated genotoxicity/oncogenicity
AIDS gene therapy:
Antiretroviral drug therapy has reduced the morbidity and mortality from HIV infection, but despite enormous efforts there is still no effective vaccine. For AIDS stem cell gene therapy, transgenes that interfere with HIV replication are delivered to hematopoietic (blood) stem cells that are infused into a patient. These stem cells then produce mature lymphocytes and macrophages (white blood cells) that are resistant to infection. Gene therapy for AIDS has been evaluated in clinical trials, but in these studies the inability to efficiently deliver anti-HIV transgenes to stem cells has been a significant roadblock. We have developed a foamy retrovirus vector that expresses 3 anti-HIV transgenes and inhibits viral replication over 10,000-fold. This vector can be efficiently delivered to human hematopoietic stem cells as assayed in a mouse model.
Identifying genes involved in acute myeloid leukemia:
A proven way to better understand cancer mechanisms and develop targeted therapies is to identify the genes that are involved in the development and progression of cancer. We are employing a novel retroviral mutagenesis screen approach designed to rapidly identify genes that are involved in the development of myelodysplastic syndromes (MDS) and progression to acute myeloid leukemia (AML). One goal of this research is to develop biomarkers that can be used to identify MDS/AML patients that respond to specific types of therapy. A second goal is to identify gene products that can be therapeutically targeted in future studies with novel small molecule drugs.
Vector mediated oncogenicity/genotoxicity:
An unwanted side-effect of gene therapy using integrating retroviral vectors is that they can dysregulate the expression of nearby genes including proto-oncogenes. We have used high-throughput bioinformatic approaches with PERL computer programs to identify integration sites in hematopoietic repopulating cells and to correlate these sites with known oncogenes, and to gene expression in primitive hematopoietic cells. In these studies we compared different vector types to assess their relative genotoxicity. We are currently exploring novel approaches to reduce retroviral genotoxicity.
Identification of hematopoietic stem cell engraftment genes in gene therapy studies. Powers JM, Trobridge GD. Journal of Stem Cell Research & Therapy. 2013, S3:004. 104172/2157-7633.S3-004
Extended survival of glioblastoma patients after chemoprotective HSC gene therapy. Science Translational Medicine. 2012, 4(133):p.133ra57.
Hematopoietic stem cell expansion facilitates multilineage engraftment in a nonhuman primate cord blood transplantation model. Experimental Hematology. 2012, 40(3)p187–196.
Novel reporter systems for facile evaluation of I-SceI-mediated genome editing. Nucleic Acids Research. 2012, 40(2)e14.
Genotoxicity of retroviral hematopoietic stem cell gene therapy. Expert Opinion on Biological Therapy. 2011, 11(5):581-593.
Differential effects of HOXB4 and NUP98-HOXA10hd on hematopoietic repopulating cells in a nonhuman primate model. Human Gene Therapy. 2011. 2(12):1475-82
Efficient generation of nonhuman primate induced pluripotent stem cells Stem Cells and Development. 2011, 20(5): 795-807.
Efficient and stable MGMT-mediated selection of long-term repopulating stem cells in nonhuman primates. Journal of Clinical Investigation. 2010, 120(7):2345-54.
A Retroviral Vector Common Integration Site between Leupaxin and Zinc Finger Protein 91 (ZFP91) Observed in Baboon Hematopoietic Repopulating Cells Experimental Hematology. 2010, 38(9):819-22.
Large animal models of hematopoietic stem cell gene therapy Gene Therapy. 2010, 17(8):939-48.
Foamy combinatorial anti-HIV vectors with MGMTP140K potently inhibit HIV-1 and SHIV replication and mediate selection in vivo Gene Therapy. 2010, 17(1):37-49.
Stable marking and transgene expression without progression to monoclonality in canine long-term hematopoietic repopulating cells transduced with lentivirus vectors Human Gene Therapy. 2010, 21(4): 397-403
Cocal pseudotyped lentiviral vectors resist inactivation by human serum and efficiently transduce primate hematopoietic repopulating cells Molecular Therapy. 2010, 18(4):725–733.
Protection of stem cell-derived lymphocytes in a primate AIDS gene therapy model PLoS ONE. 2009, 4(11): e7693.
Foamy virus vectors for gene transfer Expert Opinion on Biological Therapy. 2009, 9(11)1427-1436.
Foamy and lentiviral vectors transduce canine long-term repopulating cells at similar efficiency Human Gene Therapy. 2009, 20(5):519-523.
Genetic manipulation of hematopoietic stem cells:
Thomas' Hematopoietic Cell Transplantation, 4th edition 2009. pages 116-128. Wiley Blackwell Publishing. Eds. Appelbaum et al.
Development of foamy virus vectors:
in Viral vectors for gene therapy: methods and protocols 2002. pages 545-564. Humana Press. Ed. Curtis A. Machida
Interferon-inducible Mx proteins in fish:
in Immunological Reviews 1998. Volume 166. pages 349-363. John Wiley & Sons publishing.