TY  - JOUR
A1  - Stein, Stefan
A1  - Scholz, Simone
A1  - Schwäble, Joachim
A1  - Sadat, Mohammed A.
A1  - Modlich, Ute
A1  - Schultze-Straßer, Stephan
A1  - Diaz, Margarita
A1  - Chen-Wichmann, Linping
A1  - Müller-Kuller, Uta
A1  - Brendel, Christian
A1  - Fronza, Raffaele
A1  - Kaufmann, Kerstin B.
A1  - Naundorf, Sonja
A1  - Pech, Nancy K.
A1  - Travers, Jeffrey B.
A1  - Matute, Juan D.
A1  - Presson Jr., Robert G.
A1  - Sandusky, George E.
A1  - Kunkel, Hana
A1  - Rudolf, Eva
A1  - Dillmann, Adelina
A1  - Kalle, Christof von
A1  - Kühlcke, Klaus
A1  - Baum, Christopher
A1  - Schambach, Axel
A1  - Dinauer, Mary C.
A1  - Schmidt, Manfred
A1  - Grez, Manuel
T1  - From bench to bedside : preclinical evaluation of a self-inactivating gammaretroviral vector for the gene therapy of X-linked chronic granulomatous disease
T2  - Human gene therapy. Clinical development
N2  - 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.
Y1  - 2013
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/33765
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-337658
SN  - 2324-8637
SN  - 2324-8645
VL  - 24
IS  - 2
SP  - 86
EP  - 98
PB  - Liebert
CY  - New Rochelle, NY
ER  -