title: Retroviral WASP gene transfer into human hematopoietic stem cells reconstitutes the actin cytoskeleton in myeloid progeny cells differentiated in vitro.
abstract: OBJECTIVE
  Wiskott-Aldrich syndrome (WAS) is a primary immunodeficiency disorder characterized by recurrent infections, autoimmunity, microthrombocytopenia, and susceptibility to malignant tumors. Compared with the conventional treatment using allogeneic bone marrow transplantation, hematopoietic stem cell gene therapy might offer more specific and less toxic therapeutic options.
  
  
  METHODS
  We investigated retroviral WAS protein (WASP) gene transfer to assess functional correction and potential toxicities in human CD34(+) cells from WAS patients and healthy individuals, respectively.
  
  
  RESULTS
  WASP mRNA and protein levels were restored in CD14(+) cells derived from WASP-transduced hematopoietic stem cells. Functional reconstitution in WASP-transduced myeloid cells was documented by podosome formation and Fc gamma R-mediated phagocytosis. Importantly, overexpression of WASP in CD34(+) cells from healthy donors did not cause any discernible toxic effects.
  
  
  CONCLUSIONS
  Our studies document the feasibility of WASP gene transfer into human CD34(+) cells and suggest that the phenotype of WASP-deficient myeloid cells can be restored upon retroviral gene transfer.
authors.affiliation: Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
authors.forename: Ricardo A
authors.initials: RA
authors.lastname: Dewey
authors.forename: Inés
authors.initials: I
authors.lastname: Avedillo Díez
authors.forename: Matthias
authors.initials: M
authors.lastname: Ballmaier
authors.forename: Alexandra
authors.initials: A
authors.lastname: Filipovich
authors.forename: Johann
authors.initials: J
authors.lastname: Greil
authors.forename: Tayfun
authors.initials: T
authors.lastname: Güngör
authors.forename: Christoph
authors.initials: C
authors.lastname: Happel
authors.forename: Alexey
authors.initials: A
authors.lastname: Maschan
authors.forename: Fatih
authors.initials: F
authors.lastname: Noyan
authors.forename: Ulrich
authors.initials: U
authors.lastname: Pannicke
authors.forename: Klaus
authors.initials: K
authors.lastname: Schwarz
authors.forename: Scott
authors.initials: S
authors.lastname: Snapper
authors.forename: Karl
authors.initials: K
authors.lastname: Welte
authors.forename: Christoph
authors.initials: C
authors.lastname: Klein
mesh_terms: D008841:Actin Cytoskeleton / Q000235:genetics / Q000378:metabolism*; D018952:Antigens, CD34; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D015316:Genetic Therapy; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D023461:Myeloid Progenitor Cells / Q000378:metabolism* / Q000473:pathology; D010587:Phagocytosis / Q000235:genetics; D017452:Receptors, IgG / Q000378:metabolism; D014161:Transduction, Genetic / Q000379:methods; D014923:Wiskott-Aldrich Syndrome / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D051316:Wiskott-Aldrich Syndrome Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D018952:Antigens, CD34; D018950:Lipopolysaccharide Receptors; D017452:Receptors, IgG; D051316:Wiskott-Aldrich Syndrome Protein