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.
Keywords: Allo-HSCT, CGD, EVI1, Gene therapy, Primary immunodeficiency, Retroviral vector, STAT3, Transactivation.
Current Gene Therapy
Title:Successful Combination of Sequential Gene Therapy and Rescue Allo-HSCT in Two Children with X-CGD - Importance of Timing
Volume: 15 Issue: 4
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*
Affiliation:
- Division of Immunology/Hematology/BMT, University Children`s Hospital, and Children`s Research Centre Zurich,,Swaziland
Keywords: Allo-HSCT, CGD, EVI1, Gene therapy, Primary immunodeficiency, Retroviral vector, STAT3, Transactivation.
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.
Export Options
About this article
Cite this article as:
Siler Ulrich, Paruzynski Anna, Holtgreve-Grez Heidi, Kuzmenko Elena, Koehl Ulrike, Renner D. Eleonore, Alhan Canan, van de Loosdrecht A. Arjan, Schwäble Joachim, Pfluger Thomas, Tcinda9 Joelle, Schmugge Markus, Jauch Anna, Naundorf Sonja, Kühlcke Klaus, Notheis Gundula, Güngör Tayfun, Kalle V. Christof, Schmidt Manfred, Grez Manuel, Seger Reinhard and Reichenbach Janine*, Successful Combination of Sequential Gene Therapy and Rescue Allo-HSCT in Two Children with X-CGD - Importance of Timing, Current Gene Therapy 2015; 15 (4) . https://dx.doi.org/10.2174/1566523215666150515145255
DOI https://dx.doi.org/10.2174/1566523215666150515145255 |
Print ISSN 1566-5232 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5631 |
Call for Papers in Thematic Issues
Melatonin Signaling in Health and Disease
Melatonin regulates a multitude of physiological functions, including circadian rhythms, acting as a scavenger of free radicals, an anti-inflammatory agent, a modulator of mitochondrial homeostasis, an antioxidant, and an enhancer of nitric oxide bioavailability. AANAT is the rate-limiting enzyme responsible for converting serotonin to NAS, further converted to melatonin by ...read more
Programmed Cell Death Genes in Oncology: Pioneering Therapeutic and Diagnostic Frontiers (BMS-CGT-2024-HT-45)
Programmed Cell Death (PCD) is recognized as a pivotal biological mechanism with far-reaching effects in the realm of cancer therapy. This complex process encompasses a variety of cell death modalities, including apoptosis, autophagic cell death, pyroptosis, and ferroptosis, each of which contributes to the intricate landscape of cancer development and ...read more
Related Journals
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Cancer Pharmacogenomics: Germline DNA, Tumor DNA, or Both?
Current Pharmacogenomics Lipid-Based Drug Delivery Systems for Cancer Treatment
Current Drug Targets Anticancer Drugs Designed by Mother Nature: Ancient Drugs but Modern Targets
Current Pharmaceutical Design The Inhibitor of Growth (ING) Gene Family: Potential Role in Cancer Therapy
Current Cancer Drug Targets Interaction of Human Brain Acetylcholinesterase with Cyclophosphamide: A Molecular Modeling and Docking Study
CNS & Neurological Disorders - Drug Targets Targeting Regulatory T Cells for Anticancer Therapy
Mini-Reviews in Medicinal Chemistry The Hsp32 Inhibitors SMA-ZnPP and PEG-ZnPP Exert Major Growth-Inhibitory Effects on CD34+/CD38+ and CD34+/CD38- AML Progenitor Cells
Current Cancer Drug Targets Antitumor Pharmacology - Quo Vadis ?
Current Medicinal Chemistry - Anti-Cancer Agents Targeting Microtubules to Inhibit Angiogenesis and Disrupt Tumour Vasculature:Implications for Cancer Treatment
Current Cancer Drug Targets The Coordinated Role of CYP450 Enzymes and P-gp in Determining Cancer Resistance to Chemotherapy
Current Drug Metabolism Tyrosine Kinases as Therapeutic Targets in BCR-ABL Negative Chronic Myeloproliferative Disorders
Current Drug Targets Targeting Histone Onco- Modifications Using Plant-Derived Products
Current Drug Targets Dexrazoxane for the Prevention of Cardiac Toxicity and Treatment of Extravasation Injury from the Anthracycline Antibiotics
Current Pharmaceutical Biotechnology Stem Cells Therapies in Basic Science and Translational Medicine: Current Status and Treatment Monitoring Strategies
Current Pharmaceutical Biotechnology Recent Advances for Cell / Gene Therapy in Rheumatoid Arthritis
Current Medicinal Chemistry - Anti-Inflammatory & Anti-Allergy Agents Cyclin-Dependent Kinase 4/6 (Cdk4/6) Inhibitors: Perspectives in Cancer Therapy and Imaging
Mini-Reviews in Medicinal Chemistry Urokinase Receptor (uPAR) Ligand based Recombinant Toxins for Human Cancer Therapy
Current Pharmaceutical Design Innovations and Opportunities to Improve Conventional (Deoxy)Nucleoside and Fluoropyrimidine Analogs in Cancer
Current Medicinal Chemistry The Structure and Function of Histone Deacetylases: The Target for Anti-cancer Therapy
Current Medicinal Chemistry Targeting Tumors with Small Molecule Peptides
Current Cancer Drug Targets