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: Ulrich Siler, Anna Paruzynski, Heidi Holtgreve-Grez, Elena Kuzmenko, Ulrike Koehl, Eleonore D Renner, Canan Alhan, Arjan A van de Loosdrecht, Joachim Schwäble, Thomas Pfluger, Joelle Tchinda, Markus Schmugge, Anna Jauch, Sonja Naundorf, Klaus Kühlcke, Gundula Notheis, Tayfun Güngor, Christof V Kalle, Manfred Schmidt, Manuel Grez, Reinhard Seger, Janine Reichenbach
• Journal: Current gene therapy (Curr Gene Ther) Vol. 15 Issue 4 Pg. 416-27 ( 2015) ISSN: 1875-5631 [Electronic] United Arab Emirates
• PMID: 25981636 (Publication Type: Case Reports, Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA-Binding Proteins
• MDS1 and EVI1 Complex Locus Protein
• MECOM protein, human
• Membrane Glycoproteins
• STAT3 Transcription Factor
• STAT3 protein, human
• Transcription Factors
• CYBB protein, human
• NADPH Oxidase 2
• NADPH Oxidases

Topics

• Aspergillosis (therapy)
• Aspergillus nidulans (pathogenicity)
• Child
• Chromosome Deletion
• Chromosomes, Human, Pair 7
• DNA-Binding Proteins (genetics)
• Gammaretrovirus (genetics)
• Genetic Therapy (adverse effects, methods)
• Granulomatous Disease, Chronic (therapy)
• Hematopoietic Stem Cell Transplantation (methods)
• Humans
• MDS1 and EVI1 Complex Locus Protein
• Male
• Membrane Glycoproteins (genetics)
• Myelodysplastic Syndromes (etiology)
• NADPH Oxidase 2
• NADPH Oxidases (genetics)
• Proto-Oncogenes (genetics)
• STAT3 Transcription Factor (genetics)
• Transcription Factors (genetics)