In vivo selection of retrovirally transduced hematopoietic stem cells

10.1038/2632 ◽  
1998 ◽  
Vol 4 (10) ◽  
pp. 1136-1143 ◽  
Author(s):  
James A. Allay ◽  
Derek A. Persons ◽  
Jacques Galipeau ◽  
Janice M. Riberdy ◽  
Richard A. Ashmun ◽  
...  
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Hematopoietic Stem ◽  
In Vivo Selection ◽  
Selection Of

Successful treatment of murine β-thalassemia using in vivo selection of genetically modified, drug-resistant hematopoietic stem cells

Blood ◽  
2003 ◽  
Vol 102 (2) ◽  
pp. 506-513 ◽  
Author(s):  
Derek A. Persons ◽  
Esther R. Allay ◽  
Nobukuni Sawai ◽  
Phillip W. Hargrove ◽  
Thomas P. Brent ◽  
...  
Keyword(s):  
Stem Cells ◽  
Gene Transfer ◽  
Hematopoietic Stem Cells ◽  
Bone Marrow Cells ◽  
Lentiviral Vector ◽  
Drug Resistant ◽  
Hematopoietic Stem ◽  
In Vivo Selection ◽  
Selection Of

AbstractSuccessful gene therapy of β-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, using a murine model of β-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 β-thalassemic mice given nonmyeloablative pretransplantation 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 with untreated control animals. These results were extended using a novel γ-globin/MGMT dual gene lentiviral vector. Following drug treatment, normal mice that received transduced cells had an average 67-fold increase in γ-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 β-thalassemia.

scholarly journals Protection and in Vivo Selection of Hematopoietic Stem Cells Using Temozolomide, O6-Benzylguanine, and an Alkyltransferase-Expressing Retroviral Vector

2001 ◽  
Vol 3 (1) ◽  
pp. 78-87 ◽  
Author(s):  
Nobukuni Sawai ◽  
Sheng Zhou ◽  
Elio F. Vanin ◽  
Peter Houghton ◽  
Thomas P. Brent ◽  
...  
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Retroviral Vector ◽  
Hematopoietic Stem ◽  
In Vivo Selection ◽  
Selection Of
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