title: Successful Combination of Sequential Gene Therapy and Rescue Allo-HSCT in Two Children with X-CGD - Importance of Timing.
abstract: We report on a series of sequential events leading to long-term survival and cure of pediatric X-linked chronic granulomatous disease (X-CGD) patients after gamma-retroviral gene therapy (GT) and rescue HSCT. Due to therapyrefractory life-threatening infections requiring hematopoietic stem cell transplantation (HSCT) but absence of HLAidentical donors, we treated 2 boys with X-CGD by GT. Following GT both children completely resolved invasive Aspergillus nidulans infections. However, one child developed dual insertional activation of ecotropic viral integration site 1 (EVI1) and signal transducer and activator of transcription 3 (STAT3) genes, leading to myelodysplastic syndrome (MDS) with monosomy 7. Despite resistance to mismatched allo-HSCT with standard myeloablative conditioning, secondary intensified rescue allo-HSCT resulted in 100 % donor chimerism and disappearance of MDS. The other child did not develop MDS despite expansion of a clone with a single insertion in the myelodysplasia syndrome 1 (MDS1) gene and was cured by early standard allo-HSCT. The slowly developing dominance of clones harboring integrations in MDS1-EVI1 may guide clinical intervention strategies, i.e. early rescue allo-HSCT, prior to malignant transformation. GT was essential for both children to survive and to clear therapy-refractory infections, and future GT with safer lentiviral self-inactivated (SIN) vectors may offer a therapeutic alternative for X-CGD patients suffering from life-threatening infections and lacking HLA-identical HSC donors.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Siler
authors.forename: Anna
authors.initials: A
authors.lastname: Paruzynski
authors.forename: Heidi
authors.initials: H
authors.lastname: Holtgreve-Grez
authors.forename: Elena
authors.initials: E
authors.lastname: Kuzmenko
authors.forename: Ulrike
authors.initials: U
authors.lastname: Koehl
authors.forename: Eleonore D
authors.initials: ED
authors.lastname: Renner
authors.forename: Canan
authors.initials: C
authors.lastname: Alhan
authors.forename: Arjan A van
authors.initials: AA
authors.lastname: de Loosdrecht
authors.forename: Joachim
authors.initials: J
authors.lastname: Schwäble
authors.forename: Thomas
authors.initials: T
authors.lastname: Pfluger
authors.forename: Joelle
authors.initials: J
authors.lastname: Tchinda
authors.forename: Markus
authors.initials: M
authors.lastname: Schmugge
authors.forename: Anna
authors.initials: A
authors.lastname: Jauch
authors.forename: Sonja
authors.initials: S
authors.lastname: Naundorf
authors.forename: Klaus
authors.initials: K
authors.lastname: Kühlcke
authors.forename: Gundula
authors.initials: G
authors.lastname: Notheis
authors.forename: Tayfun
authors.initials: T
authors.lastname: Güngor
authors.forename: Christof V
authors.initials: CV
authors.lastname: Kalle
authors.forename: Manfred
authors.initials: M
authors.lastname: Schmidt
authors.forename: Manuel
authors.initials: M
authors.lastname: Grez
authors.forename: Reinhard
authors.initials: R
authors.lastname: Seger
authors.affiliation: University Children's Hospital Zurich, Div. of Immunology, Steinwiesstr. 75, CH-8032 Zurich. janine.reichenbach@kispi.uzh.ch.
authors.forename: Janine
authors.initials: J
authors.lastname: Reichenbach
mesh_terms: D001228:Aspergillosis / Q000628:therapy; D001233:Aspergillus nidulans / Q000472:pathogenicity; D002648:Child; D002872:Chromosome Deletion; D002897:Chromosomes, Human, Pair 7; D004268:DNA-Binding Proteins / Q000235:genetics; D017988:Gammaretrovirus / Q000235:genetics; D015316:Genetic Therapy / Q000009:adverse effects / Q000379:methods*; D006105:Granulomatous Disease, Chronic / Q000628:therapy*; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006801:Humans; D000074008:MDS1 and EVI1 Complex Locus Protein; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics; D009190:Myelodysplastic Syndromes / Q000209:etiology; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics; D011519:Proto-Oncogenes / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D000074008:MDS1 and EVI1 Complex Locus Protein; C063575:MECOM protein, human; D008562:Membrane Glycoproteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D014157:Transcription Factors; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases