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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-GTIE-A (01))
Program Officer
Johnson, David R
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Seattle Children's Hospital
United States
Zip Code
Jacobs, Holly M; Thouvenel, Christopher D; Leach, Sarah et al. (2016) Cutting Edge: BAFF Promotes Autoantibody Production via TACI-Dependent Activation of Transitional B Cells. J Immunol 196:3525-31
Jackson, Shaun W; Scharping, Nicole E; Jacobs, Holly M et al. (2016) Cutting Edge: BAFF Overexpression Reduces Atherosclerosis via TACI-Dependent B Cell Activation. J Immunol 197:4529-4534
Jackson, Shaun W; Jacobs, Holly M; Arkatkar, Tanvi et al. (2016) B cell IFN-γ receptor signaling promotes autoimmune germinal centers via cell-intrinsic induction of BCL-6. J Exp Med 213:733-50
Metzler, Genita; Kolhatkar, Nikita S; Rawlings, David J (2015) BCR and co-receptor crosstalk facilitate the positive selection of self-reactive transitional B cells. Curr Opin Immunol 37:46-53
Jackson, Shaun W; Kolhatkar, Nikita S; Rawlings, David J (2015) B cells take the front seat: dysregulated B cell signals orchestrate loss of tolerance and autoantibody production. Curr Opin Immunol 33:70-7
Kolhatkar, Nikita S; Brahmandam, Archana; Thouvenel, Christopher D et al. (2015) Altered BCR and TLR signals promote enhanced positive selection of autoreactive transitional B cells in Wiskott-Aldrich syndrome. J Exp Med 212:1663-77
Tampella, Giacomo; Kerns, Hannah M; Niu, Deqiang et al. (2015) The Tec Kinase-Regulated Phosphoproteome Reveals a Mechanism for the Regulation of Inhibitory Signals in Murine Macrophages. J Immunol 195:246-56
Kolhatkar, Nikita S; Scharping, Nicole E; Sullivan, Jenna M et al. (2015) B-cell intrinsic TLR7 signals promote depletion of the marginal zone in a murine model of Wiskott-Aldrich syndrome. Eur J Immunol 45:2773-9
Strom, Ted S (2015) Numerical analysis of in vivo platelet consumption data from ITP patients. BMC Hematol 15:14
Jackson, Shaun W; Scharping, Nicole E; Kolhatkar, Nikita S et al. (2014) Opposing impact of B cell-intrinsic TLR7 and TLR9 signals on autoantibody repertoire and systemic inflammation. J Immunol 192:4525-32

Showing the most recent 10 out of 29 publications