title: From bench to bedside: preclinical evaluation of a self-inactivating gammaretroviral vector for the gene therapy of X-linked chronic granulomatous disease.
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.
authors.affiliation: Institute for Biomedical Research, Georg-Speyer-Haus, 60596 Frankfurt, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Stein
authors.forename: Simone
authors.initials: S
authors.lastname: Scholz
authors.forename: Joachim
authors.initials: J
authors.lastname: Schwäble
authors.forename: Mohammed A
authors.initials: MA
authors.lastname: Sadat
authors.forename: Ute
authors.initials: U
authors.lastname: Modlich
authors.forename: Stephan
authors.initials: S
authors.lastname: Schultze-Strasser
authors.forename: Margarita
authors.initials: M
authors.lastname: Diaz
authors.forename: Linping
authors.initials: L
authors.lastname: Chen-Wichmann
authors.forename: Uta
authors.initials: U
authors.lastname: Müller-Kuller
authors.forename: Christian
authors.initials: C
authors.lastname: Brendel
authors.forename: Raffaele
authors.initials: R
authors.lastname: Fronza
authors.forename: Kerstin B
authors.initials: KB
authors.lastname: Kaufmann
authors.forename: Sonja
authors.initials: S
authors.lastname: Naundorf
authors.forename: Nancy K
authors.initials: NK
authors.lastname: Pech
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Travers
authors.forename: Juan D
authors.initials: JD
authors.lastname: Matute
authors.forename: Robert G
authors.initials: RG
authors.lastname: Presson
authors.forename: George E
authors.initials: GE
authors.lastname: Sandusky
authors.forename: Hana
authors.initials: H
authors.lastname: Kunkel
authors.forename: Eva
authors.initials: E
authors.lastname: Rudolf
authors.forename: Adelina
authors.initials: A
authors.lastname: Dillmann
authors.forename: Christof
authors.initials: C
authors.lastname: von Kalle
authors.forename: Klaus
authors.initials: K
authors.lastname: Kühlcke
authors.forename: Christopher
authors.initials: C
authors.lastname: Baum
authors.forename: Axel
authors.initials: A
authors.lastname: Schambach
authors.forename: Mary C
authors.initials: MC
authors.lastname: Dinauer
authors.forename: Manfred
authors.initials: M
authors.lastname: Schmidt
authors.forename: Manuel
authors.initials: M
authors.lastname: Grez
mesh_terms: D000818:Animals; D001232:Aspergillus fumigatus / Q000472:pathogenicity; D002478:Cells, Cultured; D019175:DNA Methylation; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D017988:Gammaretrovirus / Q000235:genetics*; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism*; D006105:Granulomatous Disease, Chronic / Q000628:therapy*; D006801:Humans; D008171:Lung Diseases / Q000382:microbiology / Q000473:pathology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D011401:Promoter Regions, Genetic; D051578:Proto-Oncogene Proteins c-fes / Q000235:genetics; D013481:Superoxides / Q000378:metabolism
chemical_list: D008562:Membrane Glycoproteins; D013481:Superoxides; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D051578:Proto-Oncogene Proteins c-fes