UW-Trobridge

UW Oncology

UW Center for
AIDS Research

Northwest
Genome
Engineering
Consortium

American
Society of
Gene & Cell
Therapy
UCSC Genome
Bioinformatics
Sanger Cancer
Genome Project
Learning PERL

Foamy virus

Dr. Trobridge's
publications
on PubMed

Grant D. Trobridge
Research Assistant Professor of Medicine
University of Washington Division of Oncology

Fred Hutchinson
Cancer Research Center
1100 Fairview Ave. N.
Mailstop D1-100
Seattle, WA 98109-1024

gtrob@u.washington.edu

PhD in Microbiology, Oregon State University

Research Interests
Hematopoietic stem cell gene therapy
Foamy vectors
Vector-mediated genotoxicity/oncogenicity

Current research projects
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.

Gene therapy for Pyruvate Kinase Deficiency:
Immunodeficiencies such as ADA and SCID have been cured by gene therapy, but for these diseases efficient gene transfer is not required because corrected cells have a selective advantage. Pyruvate Kinase Deficiency, a disease of red blood cells, will likely require efficient gene transfer and is thus also an excellent model for more prevalent erythroid diseases such as thalassemias. We are developing erythroid-specific foamy vectors that express pyruvate kinase and also MGMTP140K to increase the percentage of corrected cells into a therapeutic range after transplantation.

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 now interested in using vectors to identify novel genes that are involved in hematopoiesis and cancer.

Recent Publications

Cocal pseudotyped lentiviral vectors resist inactivation by human serum and efficiently transduce primate hematopoietic repopulating cells
Molecular Therapy. In Press.

Protection of stem cell-derived lymphocytes in a primate AIDS gene therapy model
PLoS ONE. 2009, 4(11): e7693.

Foamy combinatorial anti-HIV vectors with MGMTP140K potently inhibit HIV-1 and SHIV replication and mediate selection in vivo
Gene Therapy. Epub. Sep 2009, PMID: 19741733.

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.

Long-term polyclonal and multilineage engraftment of methylguanine methyltransferase P140K gene-modified dog hematopoietic cells in primary and secondary recipients
Blood. 2009, 113(21):5094-5103.

Ex vivo expansion and lentiviral transduction of Macaca nemestrina CD4 T cells
Journal of Medical Primatology. Epub. Sep 2009, PMID: 19793180.

Efficient transduction of pigtailed macaque hematopoietic repopulating cells with HIV-based lentiviral vectors
Blood. 2008, 111(12):5537-5543.

High incidence of leukemia in large animals after stem cell gene therapy with a HOXB4-expressing retroviral vector
Journal of Clinical Investigation. 2008, 118(4): 1502-1510.

Comparison of HIV-derived lentiviral and MLV-based gammaretroviral vector integration sites in primate repopulating cells
Molecular Therapy. 2007, 15(7): 1356–1365.

Unique integration profiles of gammaretrovirus, lentivirus, and foamy virus transduced dog long-term repopulating cells
Human Gene Therapy. 2007, 18(5): 423-434.

Foamy virus-mediated gene transfer to canine repopulating cells
Blood. 2007, 109(1): 65-70.

Foamy virus vector integration sites in normal human cells
PNAS. 2006, 103(5): 1498-1503.

Book chapters

Genetic manipulation of hematopoietic stem cells.
in 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.

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Last Updated:
11/03/09

UW Oncology UW Center for AIDS Research Northwest Genome Engineering Consortium American Society of Gene & Cell Therapy UCSC Genome Bioinformatics Sanger Cancer Genome Project Learning PERL Foamy virus Dr. Trobridge's publications on PubMed	Grant D. Trobridge Research Assistant Professor of Medicine University of Washington Division of Oncology
	Fred Hutchinson Cancer Research Center 1100 Fairview Ave. N. Mailstop D1-100 Seattle, WA 98109-1024 gtrob@u.washington.edu
	PhD in Microbiology, Oregon State University Research Interests Hematopoietic stem cell gene therapy Foamy vectors Vector-mediated genotoxicity/oncogenicity Current research projects 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. Gene therapy for Pyruvate Kinase Deficiency: Immunodeficiencies such as ADA and SCID have been cured by gene therapy, but for these diseases efficient gene transfer is not required because corrected cells have a selective advantage. Pyruvate Kinase Deficiency, a disease of red blood cells, will likely require efficient gene transfer and is thus also an excellent model for more prevalent erythroid diseases such as thalassemias. We are developing erythroid-specific foamy vectors that express pyruvate kinase and also MGMTP140K to increase the percentage of corrected cells into a therapeutic range after transplantation. 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 now interested in using vectors to identify novel genes that are involved in hematopoiesis and cancer. Recent Publications Cocal pseudotyped lentiviral vectors resist inactivation by human serum and efficiently transduce primate hematopoietic repopulating cells Molecular Therapy. In Press. Protection of stem cell-derived lymphocytes in a primate AIDS gene therapy model PLoS ONE. 2009, 4(11): e7693. Foamy combinatorial anti-HIV vectors with MGMTP140K potently inhibit HIV-1 and SHIV replication and mediate selection in vivo Gene Therapy. Epub. Sep 2009, PMID: 19741733. 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. Long-term polyclonal and multilineage engraftment of methylguanine methyltransferase P140K gene-modified dog hematopoietic cells in primary and secondary recipients Blood. 2009, 113(21):5094-5103. Ex vivo expansion and lentiviral transduction of Macaca nemestrina CD4 T cells Journal of Medical Primatology. Epub. Sep 2009, PMID: 19793180. Efficient transduction of pigtailed macaque hematopoietic repopulating cells with HIV-based lentiviral vectors Blood. 2008, 111(12):5537-5543. High incidence of leukemia in large animals after stem cell gene therapy with a HOXB4-expressing retroviral vector Journal of Clinical Investigation. 2008, 118(4): 1502-1510. Comparison of HIV-derived lentiviral and MLV-based gammaretroviral vector integration sites in primate repopulating cells Molecular Therapy. 2007, 15(7): 1356–1365. Unique integration profiles of gammaretrovirus, lentivirus, and foamy virus transduced dog long-term repopulating cells Human Gene Therapy. 2007, 18(5): 423-434. Foamy virus-mediated gene transfer to canine repopulating cells Blood. 2007, 109(1): 65-70. Foamy virus vector integration sites in normal human cells PNAS. 2006, 103(5): 1498-1503.
	Book chapters Genetic manipulation of hematopoietic stem cells. in 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.

BACK TO TOP Last Updated: 11/03/09