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.
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.
|Abraham, Allistair; Kim, Yoon-Sang; Zhao, Huifen et al. (2016) Increased Engraftment of Human Short Term Repopulating Hematopoietic Cells in NOD/SCID/IL2rÎ³null Mice by Lentiviral Expression of NUP98-HOXA10HD. PLoS One 11:e0147059|
|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 43:346-51|
|Pestina, Tamara I; Hargrove, Phillip W; Zhao, Huifen et al. (2015) Amelioration of murine sickle cell disease by nonablative conditioning and Î³-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|
|Jackson, Shaun W; Scharping, Nicole E; Kolhatkar, Nikita S et al. (2014) Opposing impact of B cell-intrinsic TLR7 and TLR9 signals on autoantibody repertoire and systemic inflammation. J Immunol 192:4525-32|
|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|
|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|
|Yu, Hui; Neale, Geoffrey; Zhang, Hui et al. (2014) Downregulation of Prdm16 mRNA is a specific antileukemic mechanism during HOXB4-mediated HSC expansion in vivo. Blood 124:1737-47|
|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 22:244-5|
|Moreno-GarcÃa, Miguel E; Sommer, Karen; Rincon-Arano, Hector et al. (2013) Kinase-independent feedback of the TAK1/TAB1 complex on BCL10 turnover and NF-ÎºB activation. Mol Cell Biol 33:1149-63|
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