This proposal seeks to develop an effective and safe pre-clinical model for gene therapy in Wiskott- Aldrich Syndrome (WAS). While transplantation using HLA-matched bone marrow can be curative for young WAS patients, the success rate falls precipitously with increasing age. Multiple lines of evidence document a strong selective advantage for WASP expressing hematopoeitic cell subsets suggesting that introduction of the normal WASP gene into hematopoietic stem cells (HSC) could provide a viable therapeutic alternative in disease management. While conceptually simple, development of a safe and effective strategy for WASP gene replacement requires extensive pre-clinical modeling in human and animal systems. This proposal takes advantage of combined expertise, and a network of important research and clinical collaborators, to establish a lentiviral delivery system for the definitive genetic treatment of WAS. We will test the hypotheses that: 1) WASP activity is crucial for both the generation of marginal zone (MZ) B cells and homeostasis of functional T-regulatory cells (TR);and that these observations help to explain the susceptibility to infection with encapsulated bacteria, and the high-incidence of autoimmunity in WAS patients, respectively. Further, we predict that LV gene therapy will rescue these key defects. 2) Lentiviral vectors containing a pan-hematopoeitic or selected lymphoid restricted promoters will lead to functional correction of lymphoid development, activation, and survival;platelet turnover;and immune function in vivo in an animal model of WAS. 3) Analysis of viral marking and expression in a non-human primate model will allow us to define the optimal vector for use in human clinical trials;and provide key data with regard to any potential toxicity of this vector and/or dysregulated WASP expression within HSC and their progeny. Our proposed studies will provide nearly all of the key expression, efficacy, and safety data required to move forward with a human gene therapy trial for WAS;and have a very high likelihood for translation into new therapies.
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