|
|
 Previous Article | Table of Contents | Next Article 
Blood, 15 March 2002, Vol. 99, No. 6, pp. 1902-1908
PLENARY PAPER
Successful treatment of murine  -thalassemia intermedia by
transfer of the human -globin gene
Chad May,
Stefano Rivella,
Amy Chadburn, and
Michel Sadelain
From the Department of Human Genetics/Medicine, the
Immunology Program, and the Gene Transfer and Somatic Cell Engineering
Laboratory, Memorial Sloan-Kettering Cancer Center, and the Department
of Pathology, Weill Medical College of Cornell University, New York,
New York.
The  -thalassemias are caused by more than 200 mutations
that reduce or abolish -globin production. The severity of the
resulting anemia can lead to lifelong transfusion dependency. A genetic treatment based on globin gene transfer would require that transgene expression be erythroid specific, elevated, and sustained over time. We
report here that long-term synthesis of chimeric hemoglobin (mu 2:hu ) could be achieved in mice
with -thalassemia intermedia following engraftment with bone marrow cells transduced with a lentiviral vector encoding the human
-globin gene. In the absence of any posttransduction
selection, the treated chimeras exhibit durably increased hemoglobin
levels without diminution over 40 weeks. Ineffective erythropoiesis and
extramedullary hematopoiesis (EMH) regress, as reflected by
normalization of spleen size, architecture, hematopoietic colony
formation, and disappearance of liver EMH. These findings establish
that a sustained increase of 3 to 4 g/dL hemoglobin is sufficient to
correct ineffective erythropoiesis. Hepatic iron accumulation is
markedly decreased in 1-year-old chimeras, indicating persistent
protection from secondary organ damage. These results demonstrate for
the first time that viral-mediated globin gene transfer in
hematopoietic stem cells effectively treats a severe hemoglobin disorder.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
I. V. Libani, E. C. Guy, L. Melchiori, R. Schiro, P. Ramos, L. Breda, T. Scholzen, A. Chadburn, Y. Liu, M. Kernbach, et al.
Decreased differentiation of erythroid cells exacerbates ineffective erythropoiesis in {beta}-thalassemia
Blood,
August 1, 2008;
112(3):
875 - 885.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. W. Nienhuis
Development of gene therapy for blood disorders
Blood,
May 1, 2008;
111(9):
4431 - 4444.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Moi and M. Sadelain
Towards the genetic treatment of {beta}-thalassemia: new disease models, new vectors, new cells
Haematologica,
March 1, 2008;
93(3):
325 - 330.
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. Li, S. Xie, X. Guo, X. Gong, S. Wang, D. Lin, J. Zhang, Z. Ren, S. Huang, F. Zeng, et al.
A novel transgenic mouse model produced from lentiviral germline integration for the study of {beta}-thalassemia gene therapy
Haematologica,
March 1, 2008;
93(3):
356 - 362.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S.-Y. Xie, Z.-R. Ren, J.-Z. Zhang, X.-B. Guo, Q.-X. Wang, S. Wang, D. Lin, X.-L. Gong, W. Li, S.-Z. Huang, et al.
Restoration of the balanced {alpha}/{beta}-globin gene expression in {beta}654-thalassemia mice using combined RNAi and antisense RNA approach
Hum. Mol. Genet.,
November 1, 2007;
16(21):
2616 - 2625.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
X.-D. Han, C. Lin, J. Chang, M. Sadelain, and Y. W. Kan
Fetal gene therapy of {alpha}-thalassemia in a mouse model
PNAS,
May 22, 2007;
104(21):
9007 - 9011.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Ferretti, J. C. Villaescusa, P. Di Rosa, L. C. Fernandez-Diaz, E. Longobardi, R. Mazzieri, A. Miccio, N. Micali, L. Selleri, G. Ferrari, et al.
Hypomorphic Mutation of the TALE Gene Prep1 (pKnox1) Causes a Major Reduction of Pbx and Meis Proteins and a Pleiotropic Embryonic Phenotype
Mol. Cell. Biol.,
August 1, 2006;
26(15):
5650 - 5662.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. He, Q. Yang, and L.-J. Chang
Dynamic DNA Methylation and Histone Modifications Contribute to Lentiviral Transgene Silencing in Murine Embryonic Carcinoma Cells
J. Virol.,
November 1, 2005;
79(21):
13497 - 13508.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. M. Bodine
Gene therapy for sickle cell disease marches on
Blood,
December 15, 2003;
102(13):
4247 - 4247.
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. J. Russell and K.-W. Peng
Primer on Medical Genomics Part X: Gene Therapy
Mayo Clin. Proc.,
November 1, 2003;
78(11):
1370 - 1383.
[Abstract]
[PDF]
|
|
|
|
|
|
|
C. Lutzko, D. Senadheera, D. Skelton, D. Petersen, and D. B. Kohn
Lentivirus Vectors Incorporating the Immunoglobulin Heavy Chain Enhancer and Matrix Attachment Regions Provide Position-Independent Expression in B Lymphocytes
J. Virol.,
July 1, 2003;
77(13):
7341 - 7351.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Rivella, C. May, A. Chadburn, I. Riviere, and M. Sadelain
A novel murine model of Cooley anemia and its rescue by lentiviral-mediated human beta -globin gene transfer
Blood,
April 15, 2003;
101(8):
2932 - 2939.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Baum, J. Dullmann, Z. Li, B. Fehse, J. Meyer, D. A. Williams, and C. von Kalle
Side effects of retroviral gene transfer into hematopoietic stem cells
Blood,
March 15, 2003;
101(6):
2099 - 2113.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. R. Bharadwaj, C. D. Trainor, P. Pasceri, and J. Ellis
LCR-regulated transgene expression levels depend on the Oct-1 site in the AT-rich region of beta -globin intron-2
Blood,
February 15, 2003;
101(4):
1603 - 1610.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. F. Atweh, J. DeSimone, Y. Saunthararajah, H. Fathallah, R. S. Weinberg, R. L. Nagel, M. E. Fabry, and R. J. Adams
Hemoglobinopathies
Hematology,
January 1, 2003;
2003(1):
14 - 39.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. M. Vacek, H. Ma, F. Gemignani, G. Lacerra, T. Kafri, and R. Kole
High-level expression of hemoglobin A in human thalassemic erythroid progenitor cells following lentiviral vector delivery of an antisense snRNA
Blood,
January 1, 2003;
101(1):
104 - 111.
[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]
|
|
|
|
|
