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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL072865-04
Application #
6984780
Study Section
Special Emphasis Panel (ZHL1-CSR-M (O1))
Program Officer
Werner, Ellen
Project Start
2003-12-12
Project End
2008-11-30
Budget Start
2005-12-01
Budget End
2006-11-30
Support Year
4
Fiscal Year
2006
Total Cost
$108,000
Indirect Cost
Name
University of Tennessee Health Science Center
Department
Pathology
Type
Schools of Medicine
DUNS #
941884009
City
Memphis
State
TN
Country
United States
Zip Code
38163
Marathe, Bindumadhav M; Prislovsky, Amanda; Astrakhan, Alexander et al. (2009) Antiplatelet antibodies in WASP(-) mice correlate with evidence of increased in vivo platelet consumption. Exp Hematol 37:1353-63
Prislovsky, Amanda; Marathe, Bindumadhav; Hosni, Amira et al. (2008) Rapid platelet turnover in WASP(-) mice correlates with increased ex vivo phagocytosis of opsonized WASP(-) platelets. Exp Hematol 36:609-23
Andreansky, Samita; Liu, Haiyan; Turner, Stephen et al. (2005) WASP- mice exhibit defective immune responses to influenza A virus, Streptococcus pneumoniae, and Mycobacterium bovis BCG. Exp Hematol 33:443-51