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

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, George E. Sandusky, Hana Kunkel, Eva RudolfAdelina Dillmann, Christof von Kalle, Klaus Kühlcke, Christopher Baum, Axel Schambach, Mary C. Dinauer, Manfred Schmidt, Manuel Grez

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)86-98
Number of pages13
JournalUnknown Journal
Volume24
Issue number2
DOIs
StatePublished - Jun 2013

ASJC Scopus subject areas

  • Genetics(clinical)

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    Stein, S., Scholz, S., Schwäble, J., Sadat, M. A., Modlich, U., Schultze-Strasser, S., Diaz, M., Chen-Wichmann, L., Müller-Kuller, U., Brendel, C., Fronza, R., Kaufmann, K. B., Naundorf, S., Pech, N. K., Travers, J. B., Matute, J. D., Presson, R. G., Sandusky, G. E., Kunkel, H., ... Grez, M. (2013). From bench to bedside: preclinical evaluation of a self-inactivating gammaretroviral vector for the gene therapy of X-linked chronic granulomatous disease. Unknown Journal, 24(2), 86-98. https://doi.org/10.1089/humc.2013.019