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.
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