Successful Combination of Sequential Gene Therapy and Rescue Allo-HSCT in Two Children with X-CGD - Importance of Timing

Author(s): 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 Tcinda9, Markus Schmugge, Anna Jauch, Sonja Naundorf, Klaus Kühlcke, Gundula Notheis, Tayfun Güngör, Christof V. Kalle, Manfred Schmidt, Manuel Grez, Reinhard Seger and Janine Reichenbach*

Volume 15, Issue 4, 2015

Page: [416 - 427] Pages: 12

DOI: 10.2174/1566523215666150515145255

Price: $65


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.

Keywords: Allo-HSCT, CGD, EVI1, Gene therapy, Primary immunodeficiency, Retroviral vector, STAT3, Transactivation.

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