title: Gene therapy for chronic granulomatous disease: current status and future perspectives.
abstract: Several Phase I/II clinical trials aiming at the correction of X-linked CGD by gene transfer into hematopoietic stem cells (HSCs) have demonstrated the therapeutic potential of gene modified autologous HSCs for the treatment of CGD. Resolution of therapy-resistant bacterial and fungal infections in liver, lung and spinal canal of CGD patients were clearly documented in all trials. However, clinical benefits were not sustained over time due to the failure of gene transduced cells to engraft long-term. Moreover, severe adverse effects were observed in some of the treated patients due to insertional mutagenesis leading to the activation of growth promoting genes and to myeloid malignancy. These setbacks fostered the development of novel safety and efficacy improved vectors that have already entered or are about to enter the clinics. Meanwhile, ongoing research is constantly refining the CGD disease phenotype, including the definition of factors that may explain the unique engraftment phenotype observed in CGD gene therapy trials. This review provides a condensed overview on the current knowledge of the molecular pathomechanisms and clinical manifestations of CGD and summarizes the lessons learned from clinical gene therapy trials, the preclinical progress in vector design and the future perspectives for the gene therapy of CGD.
authors.forename: Kerstin B
authors.initials: KB
authors.lastname: Kaufmann
authors.forename: Maria
authors.initials: M
authors.lastname: Chiriaco
authors.forename: Ulrich
authors.initials: U
authors.lastname: Siler
authors.forename: Andrea
authors.initials: A
authors.lastname: Finocchi
authors.forename: Janine
authors.initials: J
authors.lastname: Reichenbach
authors.forename: Stefan
authors.initials: S
authors.lastname: Stein
authors.affiliation: Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, 60596 Frankfurt, Germany. grez@gsh.unifrankfurt.de.
authors.forename: Manuel
authors.initials: M
authors.lastname: Grez
mesh_terms: D000818:Animals; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000627:therapeutic use*; D006105:Granulomatous Disease, Chronic / Q000235:genetics* / Q000628:therapy*; D006801:Humans