Lentiviral Gene Therapy for Wiskott-Aldrich Syndrome

Seattle Children'S Hospital, Seattle WA

Investigators

Linked publications & trials

Abstract

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 safe and effective, 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) Incorporation of an insulator into these vectors will facilitate WASP expression, reduce the risk of viral enhancer mutagenesis, and rescue function with a minimum number of viral integrations per gene corrected cell. 4) 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.