Gene Therapy for the Wiskott Aldrich Syndrome

University Of Tennessee Health Sci Ctr, Memphis TN

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): The goal of this application is the development of an effective and safe methodology for treating hematopoietic diseases with gene therapy. The work is focused on a murine model of the Wiskott-Aldrich syndrome (WAS), which in humans causes the triad of eczema, immunodeficiency and thrombocytopenia due to deficiency of the WAS protein (WASP). Although curable by bone marrow transplantation, many patients with WAS lack a suitable donor, and therefore alternative therapeutic approaches are required. The murine model faithfully reproduces the human condition with respect to immunodeficiency and thrombocytopenia. The applicant's preliminary data have established sensitivity to challenge with mycobacterium bovis and influenza in the murine WAS model providing quantifiable assays for evaluating the effects of gene transfer. Four specific aims are proposed: 1) to correct the immunodeficiency of murine WAS; 2) to determine the degree of myeloablation required to achieve phenotypic correction of immune function in murine WAS; 3) to correct the thrombocytopenia of murine WAS; and 4) to evaluate the mechanisms responsible for murine WAS thrombocytopenia. The studies are focused on correlating the pattern of and levels of WASP expression in various hematopoietic lineages with phenotypic correction of the immunodeficiency and thrombocytopenia. If necessary, various vector designs will be explored in the context of optimizing the outcome of the gene therapy intervention. Quantitative data generated in a murine model will be useful in developing future human clinical trials. The environment at St. Jude Children's Research Hospital is particularly conducive to training in these areas. Areas of relevant expertise include the use of oncoretroviral vectors to correct immunodeficiencies, the development and use of oncoretroviral and lentiviral vectors to treat severe beta-thalassemia and general expertise in the development of lentiviral vectors. The applicant will also draw on outstanding expertise in congenital immunodeficiencies, in T-cell immunology and in platelet function. The proposed work will therefore allow the applicant to build upon his previous clinical training in clinical pathology and hematopathology and laboratory experience in virology and to enhance his potential for success as an independent investigator.