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 Blood, 15 June 2008, Vol. 111, No. 12, pp. 5537-5543.
Prepublished online as a Blood First Edition Paper on April 3, 2008; DOI 10.1182/blood-2007-09-115022.

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GENE THERAPY

Efficient transduction of pigtailed macaque hematopoietic repopulating cells with HIV-based lentiviral vectors

Grant D. Trobridge1,2, Brian C. Beard1, Christina Gooch1, Martin Wohlfahrt1, Philip Olsen1, James Fletcher2, Punam Malik3, and Hans-Peter Kiem1,2

1 Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA; 2 Department of Medicine, University of Washington School of Medicine, Seattle; and 3 Division of Experimental Hematology and Division of Hematology Oncology, Cincinnati Children's Hospital Medical Center, OH

Lentiviral vectors are attractive for hematopoietic stem cell (HSC) gene therapy because they do not require mitosis for nuclear entry, they efficiently transduce hematopoietic repopulating cells, and self-inactivating (SIN) designs can be produced at high titer. Experiments to evaluate HIV-derived lentiviral vectors in nonhuman primates prior to clinical trials have been hampered by low transduction frequencies due in part to host restriction by TRIM5{alpha}. We have established conditions for efficient transduction of pigtailed macaque (Macaca nemestrina) long-term repopulating cells using VSV-G–pseudotyped HIV-based lentiviral vectors. Stable, long-term, high-level gene marking was observed in 3 macaques using relatively low MOIs (5-10) in a 48-hour ex vivo transduction protocol. All animals studied had rapid neutrophil engraftment with a median of 10.3 days to a count greater than 0.5 x 109/L (500/µL). Expression was detected in all lineages, with long-term marking levels in granulocytes at approximately 20% to 30%, and in lymphocytes at approximately 12% to 23%. All animals had polyclonal engraftment as determined by analysis of vector integration sites. These data suggest that lentiviral vectors should be highly effective for HSC gene therapy, particularly for diseases in which maintaining the engraftment potential of stem cells using short-term ex vivo transduction protocols is critical.


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