In recent years, treatments for Sickle Cell Disease (SCD) have significantly decreased the frequency and duration of sickle cell crises and significantly lengthened the life expectancy of patients. These improvements have been due to clinical, genetic and molecular advances that have revealed basic aspects of the pathophysiology of SCD. In spite of these advances, SCD remains associated with significant mortality and morbidity. The large body of data for autologous stem cell bone marrow transplantation has shown it to be effective for a minority of patients with SCD, but early mortality, the availability of suitable donors and factors involved in patient selection remain limiting factors. As an alternative, genetic correction of SCD offers hope as a potential curative approach for the majority of patients. Recent progress in the development of mouse models of hemoglobin disorders and in lentivirus-based vector design have provided strong rationale and impetus for preclinical implementation of gene therapy approaches for SCD. In this proposal, we address three important challenges to the successful genetic correction of SCD. First, we develop lentivirus-based vectors for the transduction of human gamma-globin genes. These vectors include regulatory elements that are critical for high-level single copy gene expression and are evaluated both in transgenic mice and model cell lines. Second, we evaluate their transduction efficiency into bone marrow-derived hematopoietic stem cells from SCD patients. And third, we evaluate these transduced cells in vivo using a human/mouse xenograft model of bone marrow transplantation. The preclinical data obtained from these experiments will serve as the rational basis for the implementation of future clinical gene therapy protocols aimed at the genetic correction of SCD.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54HL070588-05
Application #
7409092
Study Section
Special Emphasis Panel (ZHL1)
Project Start
Project End
Budget Start
2007-04-01
Budget End
2008-03-31
Support Year
5
Fiscal Year
2007
Total Cost
$352,847
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Type
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
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Dale, Juanita Conkin; Cochran, Cindy J; Roy, Lonnie et al. (2011) Health-related quality of life in children and adolescents with sickle cell disease. J Pediatr Health Care 25:208-15
McCavit, Timothy L; Quinn, Charles T; Techasaensiri, Chonnamet et al. (2011) Increase in invasive Streptococcus pneumoniae infections in children with sickle cell disease since pneumococcal conjugate vaccine licensure. J Pediatr 158:505-7
Quinn, Charles T; Stuart, Marie J; Kesler, Karen et al. (2011) Tapered oral dexamethasone for the acute chest syndrome of sickle cell disease. Br J Haematol 155:263-7
Becker, Amy M (2011) Sickle cell nephropathy: challenging the conventional wisdom. Pediatr Nephrol 26:2099-109
Neelam, Sudha; Kakhniashvili, David G; Wilkens, Stephan et al. (2011) Functional 20S proteasomes in mature human red blood cells. Exp Biol Med (Maywood) 236:580-91
Ghatpande, Swati S; Choudhary, Pankaj K; Quinn, Charles T et al. (2010) In vivo pharmaco-proteomic analysis of hydroxyurea induced changes in the sickle red blood cell membrane proteome. J Proteomics 73:619-26

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