Retrovirus gene therapy for X-linked chronic granulomatous disease can achieve stable long-term correction of oxidase activity in peripheral blood neutrophils

• Published in: Blood 2010-01, Vol.115 (4), p.783-791
• Main Authors: Kang, Elizabeth M., Choi, Uimook, Theobald, Narda, Linton, Gilda, Long Priel, Debra A., Kuhns, Doug, Malech, Harry L.
• Format: Article
• Language: English
• Subjects: Adult; Aspergillosis - therapy; Biological and medical sciences; Busulfan - therapeutic use; Chromosomes, Human, X - genetics; Combined Modality Therapy; Gene Therapy; Genetic Therapy - methods; Granulomatous Disease, Chronic - genetics; Granulomatous Disease, Chronic - metabolism; Granulomatous Disease, Chronic - therapy; Hematologic and hematopoietic diseases; Hematopoietic Stem Cell Transplantation; Humans; Immunodeficiencies; Immunodeficiencies. Immunoglobulinopathies; Immunopathology; Male; Medical sciences; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; Moloney murine leukemia virus - genetics; Monocytes - enzymology; Myeloablative Agonists - therapeutic use; NADPH Oxidase 2; NADPH Oxidases - genetics; NADPH Oxidases - metabolism; Neutropenia - therapy; Neutrophils - enzymology; Other diseases. Hematologic involvement in other diseases; Oxidants - metabolism; Respiratory Burst - physiology; Staphylococcal Infections - therapy; Superoxides - metabolism; Thrombocytopenia - therapy; Transduction, Genetic; Transplantation Conditioning - methods; Transplantation, Autologous; Young Adult
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2009-05-222760

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 gp91phox, 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.