Nature Medicine
6, 652 - 658 (2000)
doi:10.1038/76225
Efficient retrovirus-mediated transfer of the multidrug resistance 1
gene into autologous human long-term repopulating hematopoietic stem cells
Rafat Abonour1, David A. Williams2, 3, 4, Lawrence Einhorn1, Kristin M. Hall5, Jun Chen5, John Coffman5, Christie M. Traycoff1, Arthur Bank5, Ikunoshin Kato6, Maureen Ward5, Stephen D. Williams1, Robert Hromas1, 2, 7, Michael J. Robertson1, Franklin O. Smith1, 2, 3, David Woo8, Bonnie Mills9, Edward F. Srour1, 2
& Kenneth Cornetta1, 2, 71
Department of Medicine, Howard Hughes Medical Institute,
Indiana University School of Medicine, 1044 W. Walnut, Rm. 402
, Indianapolis, IN, 46202, USA
2
Department of Microbiology and Immunology, Howard Hughes
Medical Institute, Indiana University School of Medicine, 1044
W. Walnut, Rm. 402, Indianapolis, IN, 46202
, USA
3
Department of Pediatrics, Howard Hughes Medical Institute,
Indiana University School of Medicine, 1044 W. Walnut, Rm. 402
, Indianapolis, IN, 46202, USA
4
Herman B Wells Center for Pediatrics Research, Howard
Hughes Medical Institute, Indiana University School of Medicine,
1044 W. Walnut, Rm. 402, Indianapolis, IN,
46202, USA
5
Columbia University, 701st,
West 168th St., HHSC16-1604, New York,
New York, 10032, USA
6
Takara Shuzo, Biomedical Group, Seta
3-4-1, Otsu, Shiga, Japan 520-2193
7
Department of Medical and Molecular Genetics, Indiana
University School of Medicine, 1044 W. Walnut, Rm. 202,
Indianapolis, Indiana 46202, USA
8
AMGEN, One Amgen Center Drive, Thousand
Oaks, California 91320-1799, USA
9
Nexell Therapeutics, 9 Parker,
Irvine, California 92618, USA
Pre-clinical studies indicate that efficient retrovirus-mediated gene transfer
into hematopoietic stem cells and progenitor cells can be achieved by co-localizing
retroviral particles and target cells on specific adhesion domains of fibronectin.
In this pilot study, we used this technique to transfer the human multidrug
resistance 1 gene into stem and progenitor cells of patients with germ cell
tumors undergoing autologous transplantation. There was efficient gene transfer
into stem and progenitor cells in the presence of recombinant fibronectin
fragment CH-296. The infusion of these cells was associated with no harmful
effects and led to prompt hematopoietic recovery. There was in vivo
vector expression, but it may have been limited by the high rate of aberrant
splicing of the multidrug resistance 1 gene in the vector. Gene marking has
persisted more than a year at levels higher than previously reported in humans.
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