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Open Access
  • © Andrea Schejtman
  • , et al.
  • 2022

Preclinical Optimization and Safety Studies of a New Lentiviral Gene Therapy for p47phox-Deficient Chronic Granulomatous Disease

  • Andrea Schejtman 1
  • Winston Vetharoy 1
  • Uimook Choi 2
  • Christine Rivat 3
  • Narda Theobald 2
  • Giuseppa Piras 1
  • Diego Leon-Rico 1
  • Karen Buckland 1
  • Elena Armenteros-Monterroso 1
  • Sara Benedetti 1
  • Michael T Ashworth 4
  • Michael Rothe 5
  • Axel Schambach 5
  • Hubert Bobby Gaspar 6
  • Elizabeth M Kang 1
  • Harry L Malech 2
  • Adrian J Thrasher 1
  • Giorgia Santilli 1
  • 1 - Molecular and Cellular Immunology Unit - UCL Great Ormond Street Institute of Child Health - University College London - London United Kingdom
  • 2 - Laboratory of Clinical Immunology and Microbiology - National Institute of Allergy and Infectious Diseases - National Institutes of Health - Bethesda - Maryland USA
  • 3 - Great Ormond Street Hospital for Children - NHS Foundation Trust - London - United Kingdom
  • 4 - Department of Histopathology - Great Ormond Street Hospital for Children - NHS Foundation Trust - London United Kingdom
  • 5 - Institute of Experimental Hematology - Hannover Medical School - Hannover - Germany
  • 6 - Orchard Therapeutics - London United Kingdom


Chronic granulomatous disease (CGD) is an inherited blood disorder of phagocytic cells that renders patients susceptible to infections and inflammation. A recent clinical trial of lentiviral gene therapy for the most frequent form of CGD, X-linked, has demonstrated stable correction over time, with no adverse events related to the gene therapy procedure. We have recently developed a parallel lentiviral vector for p47phox-deficient CGD (p47phoxCGD), the second most common form of this disease. Using this vector, we have observed biochemical correction of CGD in a mouse model of the disease. In preparation for clinical trial approval, we have performed standardized preclinical studies following Good Laboratory Practice (GLP) principles, to assess the safety of the gene therapy procedure. We report no evidence of adverse events, including mutagenesis and tumorigenesis, in human hematopoietic stem cells transduced with the lentiviral vector. Biodistribution studies of transduced human CD34+ cells indicate that the homing properties or engraftment ability of the stem cells is not negatively affected. CD34+ cells derived from a p47phoxCGD patient were subjected to an optimized transduction protocol and transplanted into immunocompromised mice. After the procedure, patient-derived neutrophils resumed their function, suggesting that gene correction was successful. These studies pave the way to a first-in-man clinical trial of lentiviral gene therapy for the treatment of p47phoxCGD.