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Braun C.J.,Ludwig Maximilians University of Munich | Boztug K.,Hannover Medical School | Boztug K.,Austrian Academy of Sciences | Paruzynski A.,German Cancer Research Center | And 27 more authors.
Science Translational Medicine | Year: 2014

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. Source

Boztug K.,Hannover Medical School | Schmidt M.,German Cancer Research Center | Schwarzer A.,Hannover Medical School | Banerjee P.P.,Childrens Hospital of Philadelphia | And 14 more authors.
New England Journal of Medicine | Year: 2010

The Wiskott-Aldrich syndrome (WAS) is an X-linked recessive primary immunodeficiency disorder associated with thrombocytopenia, eczema, and autoimmunity. We treated two patients who had this disorder with a transfusion of autologous, genetically modified hematopoietic stem cells (HSC). We found sustained expression of WAS protein expression in HSC, lymphoid and myeloid cells, and platelets after gene therapy. T and B cells, natural killer (NK) cells, and monocytes were functionally corrected. After treatment, the patients' clinical condition markedly improved, with resolution of hemorrhagic diathesis, eczema, autoimmunity, and predisposition to severe infection. Comprehensive insertion-site analysis showed vector integration that targeted multiple genes controlling growth and immunologic responses in a persistently polyclonal hematopoiesis. (Funded by Deutsche Forschungsgemeinschaft and others; German Clinical Trials Register number, DRKS00000330.). Copyright © 2010 Massachusetts Medical Society. Source

Sharapova S.O.,Belarusian Research Center for Pediatric Oncology | Guryanova I.E.,Belarusian Research Center for Pediatric Oncology | Pashchenko O.E.,Russian Clinical Childrens Hospital | Kondratenko I.V.,Russian Clinical Childrens Hospital | And 5 more authors.
Journal of Clinical Immunology | Year: 2016

Background: Omenn syndrome [Mendelian Inheritance (OMIM 603554)] is a genetic disease of the immune system, characterized by the presence of fatal generalized severe erythroderma, lymphoadenopathy, eosinophilia and profound immunodeficiency. Objective: We studied clinical and immunologic presentation of the disease manifestation among East Slavs population with genetically confirmed Omenn syndrome. Results: We collected clinical and immunologic data of 11 patients (1 from Belarus, 5 – Ukraine, 5 – Russia): 6 females, 5 males. The age of Omenn syndrome manifestation varied from the 1st day of life to 1 year and 1 month, the age of diagnosis – 20 days to 1 year and 10 months. Nine out of 11 patients had classic immunologic phenotype T(+/−)B-NK+, 1 pt had TlowB + NK+ with CD3 + TCRgd + expansion and 1 had TlowB+/−NK+ phenotype. Eight out of 11 pts had mutation in RAG1 gene, 4 out of 8 had c.368-369delAA (p.K86fsX118) in homozygous state or heterozygous compound. In our cohort of patients, we also described two new mutations in RAG genes (p.E722Q in RAG1 and p.M459R in RAG2). At present, 7/11 were transplanted and 5 out of the transplanted are alive. Conclusion: This study demonstrates that the most popular genetic abnormality in East Slavs children with Omenn syndrome is c.368-369delAA (p.K86fs118) in RAG1 gene, which may be connected with more favorable prognosis because 4/4 patients survived after hematopoietic stem cells transplantation. © 2015, Springer Science+Business Media New York. Source

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