Retrovirus gene therapy for X-linked chronic granulomatous disease can achieve stable long-term correction of oxidase activity in peripheral blood neutrophils.
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.
Kang
Elizabeth M
EM
Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. ekang@niaid.nih.gov
Choi
Uimook
U
Theobald
Narda
N
Linton
Gilda
G
Long Priel
Debra A
DA
Kuhns
Doug
D
Malech
Harry L
HL
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
D008562:Membrane Glycoproteins; D019653:Myeloablative Agonists; D016877:Oxidants; D013481:Superoxides; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D002066:Busulfan