From bench to bedside : preclinical evaluation of a self-inactivating gammaretroviral vector for the gene therapy of X-linked chronic granulomatous disease

  • Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by impaired antimicrobial activity in phagocytic cells. As a monogenic disease affecting the hematopoietic system, CGD is amenable to gene therapy. Indeed in a phase I/II clinical trial, we demonstrated a transient resolution of bacterial and fungal infections. However, the therapeutic benefit was compromised by the occurrence of clonal dominance and malignant transformation demanding alternative vectors with equal efficacy but safety-improved features. In this work we have developed and tested a self-inactivating (SIN) gammaretroviral vector (SINfes.gp91s) containing a codon-optimized transgene (gp91(phox)) under the transcriptional control of a myeloid promoter for the gene therapy of the X-linked form of CGD (X-CGD). Gene-corrected cells protected X-CGD mice from Aspergillus fumigatus challenge at low vector copy numbers. Moreover, the SINfes.gp91s vector generates substantial amounts of superoxide in human cells transplanted into immunodeficient mice. In vitro genotoxicity assays and longitudinal high-throughput integration site analysis in transplanted mice comprising primary and secondary animals for 11 months revealed a safe integration site profile with no signs of clonal dominance.

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Author:Stefan Stein, Simone Scholz, Joachim Schwäble, Mohammed A. Sadat, Ute Modlich, Stephan Schultze-Straßer, Margarita Diaz, Linping Chen-Wichmann, Uta Müller-Kuller, Christian Brendel, Raffaele Fronza, Kerstin B. Kaufmann, Sonja Naundorf, Nancy K. Pech, Jeffrey B. Travers, Juan D. Matute, Robert G. Presson Jr., George E. Sandusky, Hana Kunkel, Eva Rudolf, Adelina Dillmann, Christof von Kalle, Klaus Kühlcke, Christopher Baum, Axel Schambach, Mary C. Dinauer, Manfred Schmidt, Manuel Grez
Pubmed Id:
Parent Title (English):Human gene therapy. Clinical development
Place of publication:New Rochelle, NY
Document Type:Article
Date of Publication (online):2013/07/10
Date of first Publication:2013/07/10
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2014/05/14
Page Number:13
First Page:86
Last Page:98
Institutes:Medizin / Medizin
Angeschlossene und kooperierende Institutionen / Georg-Speyer-Haus
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoDeutsches Urheberrecht