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Sustained high-level polyclonal hematopoietic marking and transgene expression 4 years after autologous transplantation of rhesus macaques with SIV lentiviral vector-transduced CD34+ cells

 Yoo-Jin Kim  ;  Yoon-Sang Kim  ;  Andre Larochelle  ;  Gabriel Renaud  ;  Tyra G. Wolfsberg  ;  Rima Adler  ;  Robert E. Donahue  ;  Peiman Hematti  ;  Bum-Kee Hong  ;  Jean Roayaei  ;  Keiko Akagi  ;  Janice M. Riberdy  ;  Arthur W. Nienhuis  ;  Cynthia E. Dunbar  ;  Derek A. Persons 
 BLOOD, Vol.113(22) : 5434-5443, 2009 
Journal Title
Issue Date
Animals ; Antigens, CD34/metabolism* ; Biomarkers/blood* ; Cells, Cultured ; Clone Cells ; Follow-Up Studies ; Gene Expression/physiology ; Genetic Therapy/methods ; Genetic Vectors/genetics ; Green Fluorescent Proteins/genetics ; Green Fluorescent Proteins/metabolism ; Hematopoietic Stem Cell Transplantation*/methods ; Hematopoietic Stem Cells/metabolism* ; Macaca mulatta ; Simian Immunodeficiency Virus/genetics* ; Simian Immunodeficiency Virus/metabolism ; Time Factors ; Transduction, Genetic ; Transgenes*/genetics ; Transplantation, Autologous ; Treatment Outcome
We previously reported that lentiviral vectors derived from the simian immunodeficiency virus (SIV) were efficient at transducing rhesus hematopoietic repopulating cells. To evaluate the persistence of vector-containing and -expressing cells long term, and the safety implications of SIV lentiviral vector-mediated gene transfer, we followed 3 rhesus macaques for more than 4 years after transplantation with transduced CD34+ cells. All 3 animals demonstrated significant vector marking and expression of the GFP transgene in T cells, B cells, and granulocytes, with mean GFP+ levels of 6.7% (range, 3.3%-13.0%), 7.4% (4.2%-13.4%), and 5.6% (3.1%-10.5%), respectively. There was no vector silencing in hematopoietic cells over time. Vector insertion site analysis of granulocytes demonstrated sustained highly polyclonal reconstitution, with no evidence for progression to oligoclonality. A significant number of clones were found to contribute at both 1-year and 3- or 4-year time points. No vector integrations were detected in the MDS1/EVI1 region, in contrast to our previous findings with a gamma-retroviral vector. These data show that lentiviral vectors can mediate stable and efficient long-term expression in the progeny of transduced hematopoietic stem cells, with an integration profile that may be safer than that of standard Moloney murine leukemia virus (MLV)-derived retroviral vectors.
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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Yoo Jin(김유진)
Hong, Bum Kee(홍범기) ORCID logo https://orcid.org/0000-0002-6456-0184
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