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 t
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.
show moreshow less

Download full text files

Export metadata

  • Export Bibtex
  • Export RIS

Additional Services

    Share in Twitter Search Google Scholar
Metadaten
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
URN:urn:nbn:de:hebis:30:3-337658
DOI:http://dx.doi.org/10.1089/humc.2013.019
ISSN:2324-8637
ISSN:2324-8645
Pubmed Id:http://www.ncbi.nlm.nih.gov/pubmed?term=23845071
Parent Title (English):Human gene therapy. Clinical development
Publisher:Liebert
Place of publication:New Rochelle, NY
Document Type:Article
Language:English
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
Volume:24
Issue:2
Pagenumber:13
First Page:86
Last Page:98
HeBIS PPN:364928484
Institutes:Medizin
Georg-Speyer-Haus
Dewey Decimal Classification:610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License Logo Veröffentlichungsvertrag für Publikationen

$Rev: 11761 $