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Blood, 15 August 2000, Vol. 96, No. 4, pp. 1334-1341
GENE THERAPY
Mild preconditioning and low-level engraftment confer
methotrexate resistance in mice transplanted with marrow expressing
drug-resistant dihydrofolate reductase activity
Rohaizah I. James,
Christopher A. Warlick,
Miechaleen D. Diers,
Roland Gunther, and
R. Scott McIvor
From the Gene Therapy Program, Institute of Human
Genetics, Department of Genetics, Cell Biology and Development, and
Department of Laboratory Medicine and Pathology, University of
Minnesota, Minneapolis, MN.
Effective engraftment of hematopoietic cells targeted for gene
transfer is facilitated by cytoreductive preconditioning such as
high-dose total body irradiation (TBI). To minimize the adverse side
effects associated with TBI, experiments were conducted to determine
whether sublethal doses of TBI would allow sufficient engraftment of
MTX-resistant hematopoietic cells to confer survival on recipient mice
administered MTX. FVB/N animals were administered 1, 2, or 4 Gy TBI
(lethal dose, 8.5 Gy), transplanted with 107 FVB/N
transgenic marrow cells expressing an MTX-resistant dihydrofolate reductase (DHFR) transgene, and then administered MTX daily for 60 days. Control mice administered 1 Gy with or without subsequent transplantation of normal marrow cells succumbed to MTX toxicity by day
45. In contrast, nearly all animals transplanted with transgenic marrow
survived MTX administration, regardless of the TBI dose used for
preconditioning. The donor DHFR transgenic marrow engraftment level was
proportional to the preconditioning dose of TBI but was surprisingly
reduced in animals given 2 or 4 Gy TBI and subsequently administered
MTX when compared with control animals administered phosphate-buffered
saline. Animals preconditioned with 1 Gy were also protected from MTX
toxicity when transplanted with reduced amounts (5 × 106 and 1 × 106 cells) of DHFR transgenic
donor marrow, resulting in low-level (approximately 1%) engraftment.
In conclusion, very mild preconditioning allows sufficient low-level
engraftment of genetically modified stem cells for in vivo
manifestation of the modified phenotype, suggesting the usefulness of
mild preconditioning regimens in human gene therapy trials targeting
hematopoietic stem cells.
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