The Wiskott-Aldrich syndrome (WAS) is a rare X-linked recessive haematological disorder characterised by immune deficiency and microthrom bocytopenia, which arises from mutations in the WAS gene. In the absence of haematopoietic stem cell transplantation, the majority of WAS patients suffer considerable morbidity and eventually die from their disease. To enhance our understanding of the disease process and to facilitate the development of improved and standardised therapies, this is a multisciplinary proposal to investigate the natural history of the disease, and the cell biology of the WAS protein (WASp). Clinical outcomes in WAS will be assessed by longitudinal study of symptomatology, therapy, and quality of life. These parameters will be correlated with information on genotype and cellular function. The interaction of WASp with the acting cytoskeleton and cellular signalling pathways will be analysed in detail, together with processes which are highly dependant on cytoskeletal rearrangement for normal function of immune cells and platelets. On the background of this knowledge it will possible devise novel strategies based on somatic gene transfer, and to improve the quality of life for patients.
List of outcomes: 1. Clinical and Immunological database Established and curated by Partner 4 Description of a new form of disease (I-XLT), and X-linked neutropenia/myelodysplasia associated to WASP defect Description of 212 patients with WASP defects in collaboration with Prof. Ochs, Seattle, Washington University, paper submitted Publications: Notarangelo LD, Mazza C, Giliani S, D'Aria C, Gandellini F, Ravelli C, Locatelli MG, Nelson DL, Ochs HD, Notarangelo LD. Missense mutations of the WASP gene cause intermittent X-linked thrombocytopenia. Blood 2002, 99(6): 2268-9. 2. Repository of cells, cell lines and tissue Established repository of B, T cell lines and pathological specimens from WAS patients 3. Intracellular binding partners Publications: Aspenström, P. (2002). The WASP-binding protein WIRE has a role in the regulation of the actin filament system downstream of the platelet-derived growth factor receptor. Exp Cell Res 279:21-33. Aspenström, P., Fransson, Å. and Saras, J. (2003). The Rho GTPases have diverse effects on the organisation of the actin filament system. Under revision in Biochem. J. 4. Platelet and stem cell function in WAS Publications: Lacout C, Haddad E, Sabri S, Svinarchouk F, Garcon L, Capron C, Foudi A, Mzali R, Snapper SB, Louache F, Vainchenker W, Dumenil D.A defect in hematopoietic stem cell migration explains the nonrandom X-chromosome inactivation in carriers of Wiskott-Aldrich syndrome. Blood. 2003 Aug 15;102(4):1282-9. 5. B cell function in WAS Publications: Westerberg L, Greicius G, Snapper SB, Aspenstrom P, Severinson E. Cdc42, Rac1, and the Wiskott-Aldrich syndrome protein are involved in the cytoskeletal regulation of B lymphocytes. Blood 2001. 98(4): 1086-94. Westerberg, L., Wallin, R.P.A., Greicius, G., Ljunggren, H.G. and Severinson, E.: Efficient antigen presentation of soluble, but not particulate, antigen in the absence of Wiskott-Aldrich syndrome protein. Immunology 109, 384, 2003. 6. T cell function in WAS Publications: Haddad E, Zugaza JL, Louache F, Debili N, Crouin C, Schwartz K, Fischer A, Vainchenker W, Bertoglio J. The interaction between Cdc42 and WASP is required for SDF-1-induced T-lymphocyte chemotaxis. Blood 2001. 97(1): 33-8. 7. Dendritic cell and macrophage function in WAS Publications: Lorenzi R, Brickell PM, Katz DR, Kinnon C, Thrasher AJ. Wiskott-Aldrich syndrome protein is necessary for efficient IgG-mediated phagocytosis. Blood 2000. 95(9): 2943-6. Allavena P, Badolato R, Facchetti F, Vermi W, Paganin C, Luini W, Giliani S, Mazza C, Bolzern U, Chiesa I, Notarangelo L, Mantovani A, Sozzani S. Monocytes from Wiskott-Aldrich patients differentiate in functional mature dendritic cells with a defect in CD83 expression. Eur J Immunol 2001. 31(12): 3413-21. Burns S, Thrasher AJ, Blundell MP, Machesky L, Jones GE. Configuration of human dendritic cell cytoskeleton by Rho GTPases, the WAS protein, and differentiation. Blood, 2001. 98(4): 1142-9. Leverrier Y, Lorenzi R, blundell MP, Brickell P, Kinnon C, Ridley AJ, Thrasher AJ. J.Immunol 2001. 166(8): 4831-4. Jones GE, Zicha D, Dunn GA, Blundell M, Thrasher A. Restoration of podosomes and chemotaxis in Wiskott-Aldrich syndrome macrophages following induced expression of WASp. Int J Biochem Cell Biol 2002, 34(7): 806-15. Calle, Y., Jones, G.E., Jagger, C., Fuller, K., Blundell, M.P., Chambers, T., Thrasher, A.J. WASp deficiency in mice results in abnormal assembly of podosomes in osteoclasts and defects in bone resorption (in press). Burns, S., Hardy, S., Buddle, J., Yong, K., Jones, G.E., Thrasher, A.J. Maturation of DC is associated with changes in motile characteristics and adherence (in press). 8. Gene therapy feasibility 2 manuscripts in preparation (partners 1 and 7) 9. Gene therapy trial proposal Concerted action to initiate trial for WAS in Europe within the next 3-4 years after rigorous testing and safety studies. Successful clinical gene therapy studies conducted by Partner 1 in SCID-X1. 10. Optimal management guidelines Publications: Conley ME, Saragoussi D, Notarangelo L, Etzioni A, Casanova JL: An International study examining therapeutic options used in treatment of Wiskott-Aldrich syndrome. Clin Immunol, 2003, in press.
Funding SchemeCSC - Cost-sharing contracts
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