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 cancer genes using viral vectors:
Identifying the genes that are involved in the development and progression of cancer is a proven way to better understand cancer mechanisms and develop targeted therapies. We are employing a novel retroviral mutagenesis screen approach designed to rapidly identify genes that are involved in the development of breast cancer, prostate cancer and acute myeloid leukemia. One goal of this research is to develop biomarkers that can be used to identify 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. We have identified novel biomarkers for breast cancer, prostate cancer and acute myeloid leukemia using this approach.
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.
Insulated Foamy Viral Vectors. Browning DL, Collins CP, Hocum JD, Leap DJ, Rae DT, Trobridge GD. Hum Gene Ther. 2016 Mar;27(3):255-66.
Lentiviral vector-mediated insertional mutagenesis screen identifies genes that influence androgen independent prostate cancer progression and predict clinical outcome. Nalla AK, Williams TF, Collins CP, Rae DT, Trobridge GD. Mol Carcinog. 2015 Oct 29.
A novel gammaretroviral shuttle vector insertional mutagenesis screen identifies SHARPIN as a breast cancer metastasis gene and prognostic biomarker. Bii VM, Rae DT, Trobridge GD. Oncotarget. 2015 Nov 24;6(37):39507-20.
Modified Genomic Sequencing PCR Using the MiSeq Platform to Identify Retroviral Integration Sites. Rae DT, Collins CP, Hocum JD, Browning DL, Trobridge GD. Hum Gene Ther Methods. 2015 Dec;26(6):221-7.
A novel retroviral mutagenesis screen identifies prognostic genes in RUNX1 mediated myeloid leukemogenesis. Rae DT, Hocum JD, Bii V, Deeg HJ, Trobridge GD. Oncotarget. 2015 Oct 13;6(31):30664-74.
VISA–Vector Integration Site Analysis server: a web-based server to rapidly identify retroviral integration sites from next-generation sequencing. Hocum JD, Battrell LR, Maynard R, Adair JE, Beard BC, Rawlings DJ, Kiem HP, Miller DG, Trobridge GD. BMC Bioinformatics. 2015 Jul 7;16:212.
Foamy viral vector integration sites in SCID-repopulating cells after MGMTP140K-mediated in vivo selection. Olszko ME, Adair JE, Linde I, Rae DT, Trobridge P, Hocum JD, Rawlings DJ, Kiem HP, Trobridge GD. Gene Ther. 2015 Jul;22(7):591-5
A novel approach to identify driver genes involved in androgen-independent prostate cancer. Schinke EN, Bii V, Nalla A, Rae DT, Tedrick L, Meadows GG, Trobridge GD. Mol Cancer. 2014 May 23;13:120. doi: 10.1186/1476-4598-13-120.
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.