title: Gene therapy for Wiskott-Aldrich syndrome--long-term efficacy and genotoxicity.
abstract: Wiskott-Aldrich syndrome (WAS) is characterized by microthrombocytopenia, immunodeficiency, autoimmunity, and susceptibility to malignancies. In our hematopoietic stem cell gene therapy (GT) trial using a γ-retroviral vector, 9 of 10 patients showed sustained engraftment and correction of WAS protein (WASP) expression in lymphoid and myeloid cells and platelets. GT resulted in partial or complete resolution of immunodeficiency, autoimmunity, and bleeding diathesis. Analysis of retroviral insertion sites revealed >140,000 unambiguous integration sites and a polyclonal pattern of hematopoiesis in all patients early after GT. Seven patients developed acute leukemia [one acute myeloid leukemia (AML), four T cell acute lymphoblastic leukemia (T-ALL), and two primary T-ALL with secondary AML associated with a dominant clone with vector integration at the LMO2 (six T-ALL), MDS1 (two AML), or MN1 (one AML) locus]. Cytogenetic analysis revealed additional genetic alterations such as chromosomal translocations. This study shows that hematopoietic stem cell GT for WAS is feasible and effective, but the use of γ-retroviral vectors is associated with a substantial risk of leukemogenesis.
authors.affiliation: Dr. von Hauner Children's Hospital, Ludwig Maximilians University Munich, 80337 Munich, Germany.
authors.forename: Christian Jörg
authors.initials: CJ
authors.lastname: Braun
authors.forename: Kaan
authors.initials: K
authors.lastname: Boztug
authors.forename: Anna
authors.initials: A
authors.lastname: Paruzynski
authors.forename: Maximilian
authors.initials: M
authors.lastname: Witzel
authors.forename: Adrian
authors.initials: A
authors.lastname: Schwarzer
authors.forename: Michael
authors.initials: M
authors.lastname: Rothe
authors.forename: Ute
authors.initials: U
authors.lastname: Modlich
authors.forename: Rita
authors.initials: R
authors.lastname: Beier
authors.forename: Gudrun
authors.initials: G
authors.lastname: Göhring
authors.forename: Doris
authors.initials: D
authors.lastname: Steinemann
authors.forename: Raffaele
authors.initials: R
authors.lastname: Fronza
authors.forename: Claudia Regina
authors.initials: CR
authors.lastname: Ball
authors.forename: Reinhard
authors.initials: R
authors.lastname: Haemmerle
authors.forename: Sonja
authors.initials: S
authors.lastname: Naundorf
authors.forename: Klaus
authors.initials: K
authors.lastname: Kühlcke
authors.forename: Martina
authors.initials: M
authors.lastname: Rose
authors.forename: Chris
authors.initials: C
authors.lastname: Fraser
authors.forename: Liesl
authors.initials: L
authors.lastname: Mathias
authors.forename: Rudolf
authors.initials: R
authors.lastname: Ferrari
authors.forename: Miguel R
authors.initials: MR
authors.lastname: Abboud
authors.forename: Waleed
authors.initials: W
authors.lastname: Al-Herz
authors.forename: Irina
authors.initials: I
authors.lastname: Kondratenko
authors.forename: László
authors.initials: L
authors.lastname: Maródi
authors.forename: Hanno
authors.initials: H
authors.lastname: Glimm
authors.forename: Brigitte
authors.initials: B
authors.lastname: Schlegelberger
authors.forename: Axel
authors.initials: A
authors.lastname: Schambach
authors.forename: Michael Heinrich
authors.initials: MH
authors.lastname: Albert
authors.forename: Manfred
authors.initials: M
authors.lastname: Schmidt
authors.forename: Christof
authors.initials: C
authors.lastname: von Kalle
authors.forename: Christoph
authors.initials: C
authors.lastname: Klein
mesh_terms: D000293:Adolescent; D000818:Animals; D001792:Blood Platelets / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D002999:Clone Cells; D003092:Colitis / Q000209:etiology; D018450:Disease Progression; D015316:Genetic Therapy / Q000009:adverse effects*; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008214:Lymphocytes / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D009153:Mutagens / Q000009:adverse effects*; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000209:etiology / Q000473:pathology; D013921:Thrombocytopenia / Q000628:therapy; D014182:Transplantation, Autologous; D016896:Treatment Outcome; D014923:Wiskott-Aldrich Syndrome / Q000473:pathology / Q000628:therapy*; D051316:Wiskott-Aldrich Syndrome Protein / Q000235:genetics* / Q000378:metabolism / Q000627:therapeutic use*
chemical_list: D009153:Mutagens; D051316:Wiskott-Aldrich Syndrome Protein