Gene therapy for Wiskott-Aldrich syndrome-long-term efficacy and genotoxicity
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American Association for the Advancement of Science
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.
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Adolescent, Animals, Blood platelets, Child, Child, preschool, Clone cells, Colitis, Disease progression, Genetic therapy, Hematopoietic stem cell transplantation, Hematopoietic stem cells, Humans, Leukocytes, mononuclear, Lymphocytes, Mice, Mice, inbred nod, Mutagens, Precursor t-cell lymphoblastic leukemia-lymphoma, Thrombocytopenia, Transplantation, autologous, Treatment outcome, Wiskott-aldrich syndrome, Wiskott-aldrich syndrome protein, Adenosine deaminase, Immunoglobulin, Plerixafor, Recombinant granulocyte colony stimulating factor, Retrovirus vector, Actin polymerization, Acute granulocytic leukemia, Acute lymphoblastic leukemia, Animal experiment, Animal model, Antibody titer, Article, Bone marrow cell, Cell population, Chromosome translocation, Clinical article, Clinical protocol, Controlled study, Cytogenetics, Enzyme reconstitution, Fluorescence activated cell sorting, Genotoxicity, Good manufacturing practice, Hematopoiesis, High throughput sequencing, Human, Immunological synapse, Immunophenotyping, Leukemogenesis, Lymphocyte function, Lymphoid cell, Morphology, Mouse, Neutrophil, Nonhuman, Peripheral blood mononuclear cell, Preschool child, Priority journal, Protein expression, School child, Stem cell gene therapy, Thrombocyte, Transcription initiation site, Wiskott aldrich syndrome, Xenotransplantation