|
|
Blood, 15 October 2004, Vol. 104, No. 8, pp. 2281-2290.
Prepublished online as a Blood First Edition Paper on June 15, 2004; DOI 10.1182/blood-2004-03-0863.
 Previous Article | Next Article 
Submitted March 8, 2004
Accepted June 2, 2004
Extended  -Globin Locus Control Region Elements Promote Consistent Therapeutic Expression of a  -Globin Lentiviral Vector in Murine -Thalassemia
Hideki Hanawa, Phillip W Hargrove, Steven Kepes, Deo K Srivastava, Arthur W Nienhuis, and Derek A Persons*
Department of Hematology and Oncology, St. Jude Children's Research Hospital, Division of Experimental Hematology, Memphis, TN, USA
* Corresponding author; email: derek.persons{at}stjude.org.
Since increased fetal hemoglobin diminishes the severity of  -thalassemia and sickle cell anemia, a strategy using autologous, stem cell-targeted gene transfer of a  -globin gene may be therapeutically useful. We previously found that a -globin lentiviral vector utilizing the -globin promoter and elements from the -globin locus control region (LCR) totaling 1.7 kb could correct murine -thalassemia. However, therapeutic consistency was compromised by chromosomal position effects on vector expression. In contrast, we show here that the majority of animals transplanted with -thalassemic stem cells transduced with a new vector containing 3.2 kb of LCR sequences expressed high levels of fetal hemoglobin (17-33%), with an average vector copy number of 1.3. This led to a mean 2.6 g/dL increase in hemoglobin concentration and enhanced amelioration of other hematologic parameters. Analysis of clonal erythroid cells of secondary spleen colonies from transplanted mice demonstrated an increased resistance of the larger LCR vector to stable and variegating position effects. This trend was also observed for vector insertion sites located inside genes, where vector expression was often compromised, in contrast to intergenic sites, where higher levels of expression were observed. These data emphasize the importance of overcoming detrimental position effects for consistent therapeutic globin vector expression.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
H. Zhao, T. I. Pestina, M. Nasimuzzaman, P. Mehta, P. W. Hargrove, and D. A. Persons
Amelioration of murine {beta}-thalassemia through drug selection of hematopoietic stem cells transduced with a lentiviral vector encoding both {gamma}-globin and the MGMT drug-resistance gene
Blood,
June 4, 2009;
113(23):
5747 - 5756.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Miccio, R. Cesari, F. Lotti, C. Rossi, F. Sanvito, M. Ponzoni, S. J. E. Routledge, C.-M. Chow, M. N. Antoniou, and G. Ferrari
In vivo selection of genetically modified erythroblastic progenitors leads to long-term correction of {beta}-thalassemia
PNAS,
July 29, 2008;
105(30):
10547 - 10552.
[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]
|
|
|
|
|
|
|
B. Y. Ryu, M. V. Evans-Galea, J. T. Gray, D. M. Bodine, D. A. Persons, and A. W. Nienhuis
An experimental system for the evaluation of retroviral vector design to diminish the risk for proto-oncogene activation
Blood,
February 15, 2008;
111(4):
1866 - 1875.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Lisowski and M. Sadelain
Locus control region elements HS1 and HS4 enhance the therapeutic efficacy of globin gene transfer in -thalassemic mice
Blood,
December 15, 2007;
110(13):
4175 - 4178.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Rund and E. Rachmilewitz
{beta}-Thalassemia
N. Engl. J. Med.,
September 15, 2005;
353(11):
1135 - 1146.
[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]
|
|
|
|
|
