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Prepublished online as a Blood First Edition Paper on August 14, 2003; DOI 10.1182/blood-2003-05-1572.
Submitted May 20, 2003
Accepted August 4, 2003
Transient in vivo selection of transduced peripheral blood cells using antifolate drug selection in rhesus macaques transplanted with hematopoietic stem cells expressing dihydrofolate reductase vectors
Derek A Persons, James A Allay, Aylin Bonifacino, Taihe Lu, Brian Agricola, Mark E Metzger, Robert E Donahue, Cynthia E Dunbar, and Brian P Sorrentino*
Department of Hematology/Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA
Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA
* Corresponding author; email: brian.sorrentino{at}stjude.org.
One of the main obstacles for effective human gene therapy for hematopoietic disorders remains the achievement of an adequate number of genetically corrected blood cells. One approach to this goal is to incorporate drug resistance genes into vectors to enable in vivo selection of hematopoietic stem cells (HSCs). While a number of drug resistance vectors enable HSC selection in murine systems, little is known about these systems in large animal models. To address this issue, we transplanted 6 rhesus macaques with dihydrofolate resistance vectors, and studied whether selection of vector-expressing cells occurred following drug treatment with trimetrexate and nitrobenzylmercaptopurineriboside-phosphate. In some of the 10 administered drug treatment courses, substantial increases in the levels of transduced peripheral blood cells were noted, however numbers returned to baseline levels within 17 days. Attempts to induce stem cell cycling with stem cell factor and granulocyte-colony stimulating factor prior to drug treatment did not lead to sustained enrichment for transduced cells. These data highlight an important species-specific difference between murine and nonhuman primate models for assessing in vivo HSC selection strategies, and emphasize the importance of utilizing drugs capable of inducing selective pressure at the level of HSCs.
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