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

dc.contributor.authorStein, Stefan
dc.contributor.authorScholz, Simone
dc.contributor.authorSchwäble, Joachim
dc.contributor.authorSadat, Mohammed A.
dc.contributor.authorModlich, Ute
dc.contributor.authorSchultze-Strasser, Stephan
dc.contributor.authorDiaz, Margarita
dc.contributor.authorChen-Wichmann, Linping
dc.contributor.authorMüller-Kuller, Uta
dc.contributor.authorBrendel, Christian
dc.contributor.authorFronza, Raffaele
dc.contributor.authorKaufmann, Kerstin B.
dc.contributor.authorNaundorf, Sonja
dc.contributor.authorPech, Nancy K.
dc.contributor.authorTravers, Jeffrey B.
dc.contributor.authorMatute, Juan D.
dc.contributor.authorPresson, Robert G.
dc.contributor.authorSandusky, George E.
dc.contributor.authorKunkel, Hana
dc.contributor.authorRudolf, Eva
dc.contributor.authorDillmann, Adelina
dc.contributor.authorvon Kalle, Christof
dc.contributor.authorKühlcke, Klaus
dc.contributor.authorBaum, Christopher
dc.contributor.authorSchambach, Axel
dc.contributor.authorDinauer, Mary C.
dc.contributor.authorSchmidt, Manfred
dc.contributor.authorGrez, Manuel
dc.contributor.departmentPediatrics, School of Medicineen_US
dc.date.accessioned2019-08-05T15:48:36Z
dc.date.available2019-08-05T15:48:36Z
dc.date.issued2013-06
dc.description.abstractChronic 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.en_US
dc.identifier.citationStein, S., Scholz, S., Schwäble, J., Sadat, M. A., Modlich, U., Schultze-Strasser, S., … 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. Human gene therapy. Clinical development, 24(2), 86–98. doi:10.1089/humc.2013.019en_US
dc.identifier.urihttps://hdl.handle.net/1805/20177
dc.language.isoen_USen_US
dc.publisherMary Ann Lieberten_US
dc.relation.isversionof10.1089/humc.2013.019en_US
dc.relation.journalHuman Gene Therapy Clinical Developmenten_US
dc.rightsPublisher Policyen_US
dc.sourcePMCen_US
dc.subjectAspergillus fumigatusen_US
dc.subjectGenetic vectorsen_US
dc.subjectLung diseasesen_US
dc.subjectMembrane glycoproteinsen_US
dc.subjectNADPH oxidasesen_US
dc.titleFrom bench to bedside: preclinical evaluation of a self-inactivating gammaretroviral vector for the gene therapy of X-linked chronic granulomatous diseaseen_US
dc.typeArticleen_US
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