title: Ubiquitous high-level gene expression in hematopoietic lineages provides effective lentiviral gene therapy of murine Wiskott-Aldrich syndrome.
abstract: The immunodeficiency disorder Wiskott-Aldrich syndrome (WAS) leads to life-threatening hematopoietic cell dysfunction. We used WAS protein (WASp)-deficient mice to analyze the in vivo efficacy of lentiviral (LV) vectors using either a viral-derived promoter, MND, or the human proximal WAS promoter (WS1.6) for human WASp expression. Transplantation of stem cells transduced with MND-huWASp LV resulted in sustained, endogenous levels of WASp in all hematopoietic lineages, progressive selection for WASp+ T, natural killer T and B cells, rescue of T-cell proliferation and cytokine production, and substantial restoration of marginal zone (MZ) B cells. In contrast, WS1.6-huWASp LV recipients exhibited subendogenous WASp expression in all cell types with only partial selection of WASp+ T cells and limited correction in MZ B-cell numbers. In parallel, WS1.6-huWASp LV recipients exhibited an altered B-cell compartment, including higher numbers of λ-light-chain+ naive B cells, development of self-reactive CD11c+FAS+ B cells, and evidence for spontaneous germinal center (GC) responses. These observations correlated with B-cell hyperactivity and increased titers of immunoglobulin (Ig)G2c autoantibodies, suggesting that partial gene correction may predispose toward autoimmunity. Our findings identify the advantages and disadvantages associated with each vector and suggest further clinical development of the MND-huWASp LV for a future clinical trial for WAS.
authors.affiliation: Department of Immunology, University of Washington School of Medicine, Seattle, WA 98101, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Astrakhan
authors.forename: Blythe D
authors.initials: BD
authors.lastname: Sather
authors.forename: Byoung Y
authors.initials: BY
authors.lastname: Ryu
authors.forename: Socheath
authors.initials: S
authors.lastname: Khim
authors.forename: Swati
authors.initials: S
authors.lastname: Singh
authors.forename: Stephanie
authors.initials: S
authors.lastname: Humblet-Baron
authors.forename: Hans D
authors.initials: HD
authors.lastname: Ochs
authors.forename: Carol H
authors.initials: CH
authors.lastname: Miao
authors.forename: David J
authors.initials: DJ
authors.lastname: Rawlings
mesh_terms: D000818:Animals; D019070:Cell Lineage / Q000235:genetics*; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006412:Hematopoietic Stem Cells / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D016896:Treatment Outcome; D015854:Up-Regulation / Q000235:genetics; D014923:Wiskott-Aldrich Syndrome / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D051316:Wiskott-Aldrich Syndrome Protein / Q000235:genetics / Q000378:metabolism / Q000502:physiology
chemical_list: D051316:Wiskott-Aldrich Syndrome Protein