|
|
 Previous Article | Table of Contents | Next Article 
Long-Term Transfer and Expression of the Human  -Globin Gene in a Mouse Transplant Model
Harry Raftopoulos,
Maureen Ward,
Philippe Leboulch, and
Arthur Bank
From Columbia University, College of Physicians and Surgeons, the Department of Genetics and Development, the Department of Medicine, New York, New York; Massachusetts Institute of Technology, Harvard-MIT, the Division of Health Sciences and Technology, Cambridge, MA; and Harvard Medical School, Brigham and Women's Hospital, Hematology-Oncology Division, Boston, MA.
Somatic gene therapy of hemoglobinopathies depends initially on the demonstration of safe, efficient gene transfer and long-term, high-level expression of the transferred human  -globin gene in animal models. We have used a -globin gene/-locus control region retroviral vector containing several modifications to optimize gene transfer and expression in a mouse transplant model. In this report we show that transplantation of -globin-transduced hematopoietic cells into lethally irradiated mice leads to the continued presence of the gene up to 8 months posttransplantation. The transferred human -globin gene is detected in 3 of 5 mice surviving long term (>4 months) transplanted with bone marrow cells transduced with high-titer virus. Southern blotting confirms the presence of the unrearranged 5.1-kb human -globin gene-containing provirus in 2 of these mice. In addition, long-term expression of the transferred gene is seen in 2 mice at levels of 5% and 20% that of endogenous murine -globin at 6 and 8 months posttransplantation. We further document stem cell transduction by the successful transfer and high-level expression of the human -globin gene from mice transduced 9 months earlier into irradiated secondary recipient mice. These results demonstrate high-level, long-term somatic human -globin gene transfer into the hematopoietic stem cells of an animal for the first time, and suggest the potential feasibility of a retroviral gene therapy approach to sickle cell disease and the thalassemias.
Blood, Vol. 90 No. 9 (November 1), 1997:
pp. 3414-3422
© 1997 by The American Society of Hematology.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
J. C. Cheng, K. M. Sakamoto, E. M. Horwitz, S. L. Karsten, L. Shoemaker, H. I. Kornblumc, and P. Malik
Report on the Workshop "New Technologies in Stem Cell Research," Society for Pediatric Research, San Francisco, California, April 29, 2006
Stem Cells,
April 1, 2007;
25(4):
1070 - 1088.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Malik and P. I. Arumugam
Gene Therapy for {beta}-Thalassemia
Hematology,
January 1, 2005;
2005(1):
45 - 50.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Puthenveetil, J. Scholes, D. Carbonell, N. Qureshi, P. Xia, L. Zeng, S. Li, Y. Yu, A. L Hiti, J.-K. Yee, et al.
Successful correction of the human {beta}-thalassemia major phenotype using a lentiviral vector
Blood,
December 1, 2004;
104(12):
3445 - 3453.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. A. Persons, P. W. Hargrove, E. R. Allay, H. Hanawa, and A. W. Nienhuis
The degree of phenotypic correction of murine beta -thalassemia intermedia following lentiviral-mediated transfer of a human gamma -globin gene is influenced by chromosomal position effects and vector copy number
Blood,
March 15, 2003;
101(6):
2175 - 2183.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Imren, E. Payen, K. A. Westerman, R. Pawliuk, M. E. Fabry, C. J. Eaves, B. Cavilla, L. D. Wadsworth, Y. Beuzard, E. E. Bouhassira, et al.
Permanent and panerythroid correction of murine beta thalassemia by multiple lentiviral integration in hematopoietic stem cells
PNAS,
October 29, 2002;
99(22):
14380 - 14385.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. W. Emery, E. Yannaki, J. Tubb, T. Nishino, Q. Li, and G. Stamatoyannopoulos
Development of virus vectors for gene therapy of beta chain hemoglobinopathies: flanking with a chromatin insulator reduces gamma -globin gene silencing in vivo
Blood,
August 28, 2002;
100(6):
2012 - 2019.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Pawliuk, K. A. Westerman, M. E. Fabry, E. Payen, R. Tighe, E. E. Bouhassira, S. A. Acharya, J. Ellis, I. M. London, C. J. Eaves, et al.
Correction of Sickle Cell Disease in Transgenic Mouse Models by Gene Therapy
Science,
December 14, 2001;
294(5550):
2368 - 2371.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. M. Kowolik, J. Hu, and J.-K. Yee
Locus Control Region of the Human CD2 Gene in a Lentivirus Vector Confers Position-Independent Transgene Expression
J. Virol.,
May 15, 2001;
75(10):
4641 - 4648.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
D. A. Persons, E. R. Allay, D. E. Sabatino, P. Kelly, D. M. Bodine, and A. W. Nienhuis
Functional requirements for phenotypic correction of murine {beta}-thalassemia: implications for human gene therapy
Blood,
May 15, 2001;
97(10):
3275 - 3282.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. E. Sabatino, N. E. Seidel, G. J. Aviles-Mendoza, A. P. Cline, S. M. Anderson, P. G. Gallagher, and D. M. Bodine
Long-term expression of gamma -globin mRNA in mouse erythrocytes from retrovirus vectors containing the human gamma -globin gene fused to the ankyrin-1 promoter
PNAS,
November 2, 2000;
(2000)
230453097.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
D. W. Emery, E. Yannaki, J. Tubb, and G. Stamatoyannopoulos
A chromatin insulator protects retrovirus vectors from chromosomal position effects
PNAS,
July 19, 2000;
(2000)
160159597.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
D. A. Persons and A. W. Nienhuis
Gene therapy for the hemoglobin disorders: Past, present, and future
PNAS,
May 9, 2000;
97(10):
5022 - 5024.
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Grande, B. Piovani, A. Aiuti, S. Ottolenghi, F. Mavilio, and G. Ferrari
Transcriptional Targeting of Retroviral Vectors to the Erythroblastic Progeny of Transduced Hematopoietic Stem Cells
Blood,
May 15, 1999;
93(10):
3276 - 3285.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. P. Kalberer, R. Pawliuk, S. Imren, T. Bachelot, K. J. Takekoshi, M. Fabry, C. J. Eaves, I. M. London, R. K. Humphries, and P. Leboulch
From the Cover: Preselection of retrovirally transduced bone marrow avoids subsequent stem cell gene silencing and age-dependent extinction of expression of human beta -globin in engrafted mice
PNAS,
May 9, 2000;
97(10):
5411 - 5415.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. W. Emery, E. Yannaki, J. Tubb, and G. Stamatoyannopoulos
A chromatin insulator protects retrovirus vectors from chromosomal position effects
PNAS,
August 1, 2000;
97(16):
9150 - 9155.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. E. Sabatino, N. E. Seidel, G. J. Aviles-Mendoza, A. P. Cline, S. M. Anderson, P. G. Gallagher, and D. M. Bodine
Long-term expression of gamma -globin mRNA in mouse erythrocytes from retrovirus vectors containing the human gamma -globin gene fused to the ankyrin-1 promoter
PNAS,
November 21, 2000;
97(24):
13294 - 13299.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
