Lentiviral gene therapy for X-linked chronic granulomatous disease.
Donald B Kohn, Claire Booth, Elizabeth M Kang, Sung-Yun Pai, Kit L Shaw, Giorgia Santilli, Myriam Armant, Karen F Buckland, Uimook Choi, Suk See De Ravin, Morna J Dorsey, Caroline Y Kuo, Diego Leon-Rico, Christine Rivat, Natalia Izotova, Kimberly Gilmour, Katie Snell, Jinhua Xu-Bayford Dip, Jinan Darwish, Emma C Morris, Dayna Terrazas, Leo D Wang, Christopher A Bauser, Tobias Paprotka, Douglas B Kuhns, John Gregg, Hayley E Raymond, John K Everett, Geraldine Honnet, Luca Biasco, Peter E Newburger, Frederic D Bushman, Manuel Grez, H Bobby Gaspar, David A Williams, Harry L Malech, Anne Galy, Adrian J Thrasher, Net4CGD consortium
Author Information
Donald B Kohn: University of California, Los Angeles, CA, USA. dkohn@mednet.ucla.edu. ORCID
Claire Booth: Great Ormond Street Institute of Child Health and Great Ormond Street Hospital NHS Foundation Trust, London, UK.
Elizabeth M Kang: Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Sung-Yun Pai: Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Kit L Shaw: University of California, Los Angeles, CA, USA.
Giorgia Santilli: Great Ormond Street Institute of Child Health and Great Ormond Street Hospital NHS Foundation Trust, London, UK.
Myriam Armant: Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Karen F Buckland: Great Ormond Street Institute of Child Health and Great Ormond Street Hospital NHS Foundation Trust, London, UK. ORCID
Uimook Choi: Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Suk See De Ravin: Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Morna J Dorsey: University of California, San Francisco, CA, USA.
Caroline Y Kuo: University of California, Los Angeles, CA, USA.
Diego Leon-Rico: Great Ormond Street Institute of Child Health and Great Ormond Street Hospital NHS Foundation Trust, London, UK.
Christine Rivat: Great Ormond Street Institute of Child Health and Great Ormond Street Hospital NHS Foundation Trust, London, UK.
Natalia Izotova: Great Ormond Street Institute of Child Health and Great Ormond Street Hospital NHS Foundation Trust, London, UK.
Kimberly Gilmour: Great Ormond Street Institute of Child Health and Great Ormond Street Hospital NHS Foundation Trust, London, UK.
Katie Snell: Great Ormond Street Institute of Child Health and Great Ormond Street Hospital NHS Foundation Trust, London, UK.
Jinhua Xu-Bayford Dip: Great Ormond Street Institute of Child Health and Great Ormond Street Hospital NHS Foundation Trust, London, UK.
Jinan Darwish: Great Ormond Street Institute of Child Health and Great Ormond Street Hospital NHS Foundation Trust, London, UK.
Emma C Morris: University College London Hospitals NHS Foundation Trust, London, UK. ORCID
Dayna Terrazas: University of California, Los Angeles, CA, USA.
Leo D Wang: Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Christopher A Bauser: Eurofins Genomics Sequencing Europe, Konstanz, Germany. ORCID
Douglas B Kuhns: Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
John Gregg: University of Pennsylvania, Philadelphia, PA, USA.
Hayley E Raymond: University of Pennsylvania, Philadelphia, PA, USA.
John K Everett: University of Pennsylvania, Philadelphia, PA, USA.
Geraldine Honnet: Genethon, Evry, France.
Luca Biasco: Great Ormond Street Institute of Child Health and Great Ormond Street Hospital NHS Foundation Trust, London, UK.
Peter E Newburger: University of Massachusetts Medical School, Worcester, MA, USA.
Frederic D Bushman: University of Pennsylvania, Philadelphia, PA, USA. ORCID
Manuel Grez: Georg-Speyer Haus, Frankfurt, Germany.
H Bobby Gaspar: Great Ormond Street Institute of Child Health and Great Ormond Street Hospital NHS Foundation Trust, London, UK.
David A Williams: Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Harry L Malech: Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Anne Galy: Genethon, Evry, France.
Adrian J Thrasher: Great Ormond Street Institute of Child Health and Great Ormond Street Hospital NHS Foundation Trust, London, UK. a.thrasher@ucl.ac.uk. ORCID
Chronic granulomatous disease (CGD) is a rare inherited disorder of phagocytic cells. We report the initial results of nine severely affected X-linked CGD (X-CGD) patients who received ex vivo autologous CD34 hematopoietic stem and progenitor cell-based lentiviral gene therapy following myeloablative conditioning in first-in-human studies (trial registry nos. NCT02234934 and NCT01855685). The primary objectives were to assess the safety and evaluate the efficacy and stability of biochemical and functional reconstitution in the progeny of engrafted cells at 12 months. The secondary objectives included the evaluation of augmented immunity against bacterial and fungal infection, as well as assessment of hematopoietic stem cell transduction and engraftment. Two enrolled patients died within 3 months of treatment from pre-existing comorbidities. At 12 months, six of the seven surviving patients demonstrated stable vector copy numbers (0.4-1.8 copies per neutrophil) and the persistence of 16-46% oxidase-positive neutrophils. There was no molecular evidence of either clonal dysregulation or transgene silencing. Surviving patients have had no new CGD-related infections, and six have been able to discontinue CGD-related antibiotic prophylaxis. The primary objective was met in six of the nine patients at 12 months follow-up, suggesting that autologous gene therapy is a promising approach for CGD patients.
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