The overall goal of this Program Project is to develop lentiviral vectors for use in patients with sickle cell disease (SCD), Wiscott-Aldrich Syndrome (WAS), and X-linked severe combined immunodeficiency (SCIDXI). The central unifying hypothesis is that self-inactivating (SIN) lentiviral vectors containing insulator elements and appropriate intemal promoters will be both safe and effective for the treatment of these blood and immune cell disorders. Our general approach builds upon progress during the last funding period that has led to novel SEN HIV vectors for hemoglobinopathies and SCID-Xl that have a markedly lower propensity for inadvertent activation of cellular proto-oncogenes. We have also recently developed a stable lentiviral producer system that will greatly facilitate clinical vector production for all 3 disorders. In Project 1, we will generate and test improved vectors for SCD and develop new methods for expansion and transduction of hematopoietic stem cells. In Project 2, lentiviral vectors for WAS will be tested in preclinical models for efficacy and safety and later in a clinical trial of WAS gene therapy. In Project 3, an existing stable producer cell line for a SCID-Xl lentiviral vector will be used to support two clinical trials for SCID-Xl;one for newly diagnosed patients and a second trial for older children that have failed prior therapy. The Cores provide the infrastructural elements that are necessary for these 3 projects. Administrative Core A will provide general administrative support for the POl activities. Stem Cell Core B will provide the means for processing and transducing HSCs, both in preclinical experiments and in the clinical trials. Vector Core C will derive stable lentiviral producer clones for all 3 projects and provide methods for the production and certification of vectors used in the clinical trials. Immunology Core D will provide standardized immunologic reconstitution assays required for the clinical studies and assist in the recruitment and care of protocol patients. The Projects and Cores are highly synergistic and have extensive complementary interactions. Overall, we expect that the work in this proposal will lead to high impact clinical results that will define the role of lentiviral vectors for the treatment of these diseases, and that will provide pioneering information regarding the use of lentiviral vectors for human stem cell gene therapy.

Public Health Relevance

The Program Project is relevant to human health by seeking to develop new treatments for children with genetic disorders of the blood and immune system and my provide new therapies for sickle cell disease, SCID-Xl, and Wiskott Aldrich Syndrome. This Project will also produce new scientific information regarding the use of lentiviral vectors for gene therapy that may apply to other disorders.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL053749-19
Application #
8531314
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Qasba, Pankaj
Project Start
1997-09-01
Project End
2015-07-31
Budget Start
2013-09-01
Budget End
2014-07-31
Support Year
19
Fiscal Year
2013
Total Cost
$2,394,432
Indirect Cost
$964,312
Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
067717892
City
Memphis
State
TN
Country
United States
Zip Code
38105
Zhao, Hui Fen; Abraham, Allistair; Kim, Yoon-Sang et al. (2017) Lentiviral Transfer of ?-Globin with Fusion Gene NUP98-HOXA10HD Expands Hematopoietic Stem Cells and Ameliorates Murine ?-Thalassemia. Mol Ther 25:593-605
De Ravin, Suk See; Wu, Xiaolin; Moir, Susan et al. (2016) Lentiviral hematopoietic stem cell gene therapy for X-linked severe combined immunodeficiency. Sci Transl Med 8:335ra57
Abraham, Allistair; Kim, Yoon-Sang; Zhao, Huifen et al. (2016) Increased Engraftment of Human Short Term Repopulating Hematopoietic Cells in NOD/SCID/IL2r?null Mice by Lentiviral Expression of NUP98-HOXA10HD. PLoS One 11:e0147059
Wielgosz, Matthew M; Kim, Yoon-Sang; Carney, Gael G et al. (2015) Generation of a lentiviral vector producer cell clone for human Wiskott-Aldrich syndrome gene therapy. Mol Ther Methods Clin Dev 2:14063
Pestina, Tamara I; Hargrove, Phillip W; Zhao, Huifen et al. (2015) Amelioration of murine sickle cell disease by nonablative conditioning and ?-globin gene-corrected bone marrow cells. Mol Ther Methods Clin Dev 2:15045
Zhou, Sheng; Bonner, Melissa A; Wang, Yong-Dong et al. (2015) Quantitative shearing linear amplification polymerase chain reaction: an improved method for quantifying lentiviral vector insertion sites in transplanted hematopoietic cell systems. Hum Gene Ther Methods 26:4-12
Urbinati, Fabrizia; Hargrove, Phillip W; Geiger, Sabine et al. (2015) Potentially therapeutic levels of anti-sickling globin gene expression following lentivirus-mediated gene transfer in sickle cell disease bone marrow CD34+ cells. Exp Hematol 43:346-351
Treanor, Louise M; Zhou, Sheng; Janke, Laura et al. (2014) Interleukin-7 receptor mutants initiate early T cell precursor leukemia in murine thymocyte progenitors with multipotent potential. J Exp Med 211:701-13
Griffith, Linda M; Cowan, Morton J; Notarangelo, Luigi D et al. (2014) Primary Immune Deficiency Treatment Consortium (PIDTC) report. J Allergy Clin Immunol 133:335-47
De Ravin, Suk See; Gray, John T; Throm, Robert E et al. (2014) False-positive HIV PCR test following ex vivo lentiviral gene transfer treatment of X-linked severe combined immunodeficiency vector. Mol Ther 22:244-245

Showing the most recent 10 out of 152 publications