title: Retrovirus gene therapy for X-linked chronic granulomatous disease can achieve stable long-term correction of oxidase activity in peripheral blood neutrophils.
abstract: Chronic granulomatous disease (CGD) is associated with significant morbidity and mortality from infection. The first CGD gene therapy trial resulted in only short-term marking of 0.01% to 0.1% of neutrophils. A recent study, using busulfan conditioning and an SFFV retrovirus vector, achieved more than 20% marking in 2 patients with X-linked CGD. However, oxidase correction per marked neutrophil was less than normal and not sustained. Despite this, patients clearly benefited in that severe infections resolved. As such, we initiated a gene therapy trial for X-CGD to treat severe infections unresponsive to conventional therapy. We treated 3 adult patients using busulfan conditioning and an MFGS retroviral vector encoding gp91(phox), achieving early marking of 26%, 5%, and 4% of neutrophils, respectively, with sustained long-term marking of 1.1% and 0.03% of neutrophils in 2 of the patients. Gene-marked neutrophils have sustained full correction of oxidase activity for 34 and 11 months, respectively, with full or partial resolution of infection in those 2 patients. Gene marking is polyclonal with no clonal dominance. We conclude that busulfan conditioning together with an MFGS vector is capable of achieving long-term correction of neutrophil oxidase function sufficient to provide benefit in management of severe infection. This study was registered at www.clinicaltrials.gov as #NCT00394316.
authors: Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. ekang@niaid.nih.gov
authors: Elizabeth M
authors: EM
authors: Kang
authors: Uimook
authors: U
authors: Choi
authors: Narda
authors: N
authors: Theobald
authors: Gilda
authors: G
authors: Linton
authors: Debra A
authors: DA
authors: Long Priel
authors: Doug
authors: D
authors: Kuhns
authors: Harry L
authors: HL
authors: Malech
mesh_terms: D000328:Adult; D001228:Aspergillosis / Q000628:therapy; D002066:Busulfan / Q000627:therapeutic use; D041321:Chromosomes, Human, X / Q000235:genetics; D003131:Combined Modality Therapy; D015316:Genetic Therapy / Q000379:methods*; D006105:Granulomatous Disease, Chronic / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D008979:Moloney murine leukemia virus / Q000235:genetics*; D009000:Monocytes / Q000201:enzymology; D019653:Myeloablative Agonists / Q000627:therapeutic use; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics* / Q000378:metabolism; D009503:Neutropenia / Q000628:therapy; D009504:Neutrophils / Q000201:enzymology*; D016877:Oxidants / Q000378:metabolism; D016897:Respiratory Burst / Q000502:physiology; D013203:Staphylococcal Infections / Q000628:therapy; D013481:Superoxides / Q000378:metabolism; D013921:Thrombocytopenia / Q000628:therapy; D014161:Transduction, Genetic; D019172:Transplantation Conditioning / Q000379:methods; D014182:Transplantation, Autologous; D055815:Young Adult
chemical_list: D008562:Membrane Glycoproteins; D019653:Myeloablative Agonists; D016877:Oxidants; D013481:Superoxides; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D002066:Busulfan