title: Gene therapy for Wiskott-Aldrich syndrome: rescue of T-cell signaling and amelioration of colitis upon transplantation of retrovirally transduced hematopoietic stem cells in mice.
abstract: The Wiskott-Aldrich syndrome (WAS) is an X-linked primary immunodeficiency that is caused by mutations in the recently identified WASP gene. WASP plays an important role in T-cell receptor-mediated signaling to the actin cytoskeleton. In these studies we assessed the feasibility of using retroviral gene transfer into WASP-deficient hematopoietic stem cells (HSCs) to rescue the T-cell signaling defect that is characteristic of WAS. Upon transplantation of WASP-deficient (WKO) HSCs that have been transduced with WASP-expressing retroviruses, mature B and T cells developed in normal numbers. Most importantly, the defect in antigen receptor-induced proliferation was significantly improved in T cells. Moreover, the susceptibility of colitis by WKO HSCs was prevented or ameliorated in recipient bone marrow chimeras by retrovirus-mediated expression of WASP. A partial reversal of the T-cell signaling defect could also be achieved following transplantation of WASP-deficient HSCs expressing the WASP-homologous protein N-WASP. Furthermore, we have documented a selective advantage of WT over WKO cells in lymphoid tissue using competitive repopulation experiments and Southern blot analysis. Our results provide proof of principle that the WAS-associated T-cell signaling defects can be improved upon transplantation of retrovirally transduced HSCs without overt toxicity and may encourage clinical gene therapy trials.
authors.affiliation: Division of Molecular Medicine and Pediatric Hematology/Oncology, Howard Hughes Medical Institute, The Children's Hospital, Boston, MA, USA.
authors.forename: Christoph
authors.initials: C
authors.lastname: Klein
authors.forename: Deanna
authors.initials: D
authors.lastname: Nguyen
authors.forename: Ching-Hui
authors.initials: CH
authors.lastname: Liu
authors.forename: Atsushi
authors.initials: A
authors.lastname: Mizoguchi
authors.forename: Atul K
authors.initials: AK
authors.lastname: Bhan
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Miki
authors.forename: Tadaomi
authors.initials: T
authors.lastname: Takenawa
authors.forename: Fred S
authors.initials: FS
authors.lastname: Rosen
authors.forename: Fred W
authors.initials: FW
authors.lastname: Alt
authors.forename: Richard C
authors.initials: RC
authors.lastname: Mulligan
authors.forename: Scott B
authors.initials: SB
authors.lastname: Snapper
mesh_terms: D000818:Animals; D003092:Colitis / Q000209:etiology / Q000517:prevention & control / Q000628:therapy*; D015870:Gene Expression; D015316:Genetic Therapy; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins; D006410:Hematopoiesis; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D008164:Luminescent Proteins / Q000235:genetics; D008213:Lymphocyte Activation; D018655:Lymphocyte Count; D051379:Mice; D018345:Mice, Knockout; D011506:Proteins / Q000235:genetics*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D012190:Retroviridae / Q000235:genetics; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*; D014162:Transfection; D018183:Transplantation Chimera; D014923:Wiskott-Aldrich Syndrome / Q000150:complications / Q000628:therapy*; D051316:Wiskott-Aldrich Syndrome Protein
chemical_list: D008164:Luminescent Proteins; D011506:Proteins; D011948:Receptors, Antigen, T-Cell; C495768:Was protein, mouse; D051316:Wiskott-Aldrich Syndrome Protein; D049452:Green Fluorescent Proteins