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Prepublished online as a Blood First Edition Paper on March 27, 2003; DOI 10.1182/blood-2003-03-0677.
Submitted March 3, 2003
Accepted March 19, 2003
Successful treatment of murine  -thalassemia using in vivo selection of genetically-modified, drug-resistant hematopoietic stem cells
Derek A Persons*, Esther R Allay, Nobukuni Sawai, Phillip W Hargrove, Thomas P Brent, Hideki Hanawa, Arthur W Nienhuis, and Brian P Sorrentino
Department of Hematology/Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA
Department of Molecular Pharmacology, St. Jude Children's Research Hospital, Memphis, TN, USA
* Corresponding author; email: derek.persons{at}stjude.org.
Successful gene therapy of  -thalassemia will require replacement of the abnormal erythroid compartment with erythropoiesis derived from genetically corrected, autologous hematopoietic stem cells (HSCs). However, currently attainable gene transfer efficiencies into human HSCs are unlikely to yield sufficient numbers of corrected cells for a clinical benefit. Here, utilizing a murine model of -thalassemia, we demonstrate for the first time that selective enrichment in vivo of transplanted, drug-resistant HSCs can be used therapeutically and may therefore be a useful approach to overcome limiting gene transfer. We used an oncoretroviral vector to transfer a methylguanine methyltransferase (MGMT) drug-resistance gene into normal bone marrow cells. These cells were transplanted into -thalassemic mice given non-myeloablative pre-transplant conditioning with temozolomide (TMZ) and O6-benzylguanine (BG). A majority of mice receiving 2 additional courses of TMZ/BG demonstrated in vivo selection of the drug-resistant cells and amelioration of anemia, compared to untreated control animals. These results were extended using a novel  -globin/MGMT dual gene lentiviral vector. Following drug treatment, normal mice transplanted with transduced cells had an average 67-fold increase in -globin expressing red cells. These studies demonstrate that MGMT-based in vivo selection may be useful to increase genetically corrected cells to therapeutic levels in patients with -thalassemia.
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