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Canine model for gene therapy: inefficient gene expression in dogs
reconstituted with autologous marrow infected with retroviral vectors
RB Stead, WW Kwok, R Storb and AD Miller
Division of Clinical Research, Fred Hutchinson Cancer Research Center,
Seattle, WA 98104.
Successful retroviral gene transfer into murine hematopoietic stem cells
indicates the potential for somatic gene therapy in the treatment of
certain human hereditary diseases. We developed a canine model to test the
applicability of these techniques to a preclinical model of human marrow
transplantation. Previously we reported that canine CFU-GM could be
infected with retroviral vectors carrying either the gene for a mutant
dihydrofolate reductase (DHFR) or neomycin phosphotransferase (NEO). This
study reports six lethally irradiated dogs transplanted with autologous
marrow cocultivated with retroviral vector-producing cells. This procedure
conferred drug resistance to 3% to 13% of the CFU- GM. Three dogs infected
with either the NEO or DHFR virus engrafted, but we detected no
drug-resistant CFU-GM. Three dogs were given marrow infected with a DHFR
virus and received methotrexate (MTX) as in vivo selection; all three had
evidence of engraftment. In the surviving dog, we detected 0.03% to 0.1%
MTX-resistant CFU-GM at 3 to 5 weeks posttransplant during in vivo
selection. These results indicate that we can reconstitute lethally
irradiated dogs with autologous marrow exposed to retroviral vectors and
suggest that gene transfer into hematopoietic cells is feasible on a large
scale. However, the low- level transient gene expression indicates that
considerable obstacles remain before human gene therapy can be considered.
Volume 71,
Issue 3,
pp. 742-747,
03/01/1988
Copyright © 1988 by The American Society of Hematology
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