Molecular Therapy: Methods & Clinical Development (Jun 2020)
Successful Preclinical Development of Gene Therapy for Recombinase-Activating Gene-1-Deficient SCID
- Laura Garcia-Perez,
- Marja van Eggermond,
- Lieke van Roon,
- Sandra A. Vloemans,
- Martijn Cordes,
- Axel Schambach,
- Michael Rothe,
- Dagmar Berghuis,
- Chantal Lagresle-Peyrou,
- Marina Cavazzana,
- Fang Zhang,
- Adrian J. Thrasher,
- Daniela Salvatori,
- Pauline Meij,
- Anna Villa,
- Jacques J.M. Van Dongen,
- Jaap-Jan Zwaginga,
- Mirjam van der Burg,
- H. Bobby Gaspar,
- Arjan Lankester,
- Frank J.T. Staal,
- Karin Pike-Overzet
Affiliations
- Laura Garcia-Perez
- Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2333ZA Leiden, the Netherlands
- Marja van Eggermond
- Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2333ZA Leiden, the Netherlands
- Lieke van Roon
- Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2333ZA Leiden, the Netherlands
- Sandra A. Vloemans
- Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2333ZA Leiden, the Netherlands
- Martijn Cordes
- Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2333ZA Leiden, the Netherlands
- Axel Schambach
- Institute of Experimental Hematology, Hannover Medical School, 30625 Hannover, Germany
- Michael Rothe
- Institute of Experimental Hematology, Hannover Medical School, 30625 Hannover, Germany
- Dagmar Berghuis
- Willem-Alexander Children’s Hospital Department of Pediatrics, Leiden University Medical Center, 2333ZA Leiden, the Netherlands
- Chantal Lagresle-Peyrou
- Biotherapy Clinical Investigation Center, Groupe Hospitalier Universitaire Ouest, Assistance Publique-Hôpitaux de Paris, INSERM CIC 1416, Paris, France; Laboratory of Human Lymphohematopoiesis, INSERM UMR 1163, Imagine Institute and Paris Descartes University-Sorbonne Paris Cité, 75015 Paris, France; Department of Biotherapy, Necker Children’s Hospital, Assistance Publique-Hôpitaux de Paris, 75015 Paris, France
- Marina Cavazzana
- Biotherapy Clinical Investigation Center, Groupe Hospitalier Universitaire Ouest, Assistance Publique-Hôpitaux de Paris, INSERM CIC 1416, Paris, France; Laboratory of Human Lymphohematopoiesis, INSERM UMR 1163, Imagine Institute and Paris Descartes University-Sorbonne Paris Cité, 75015 Paris, France; Department of Biotherapy, Necker Children’s Hospital, Assistance Publique-Hôpitaux de Paris, 75015 Paris, France
- Fang Zhang
- Molecular and Cellular Immunology, Great Ormond Street Institute of Child Health, and Great Ormond Street Hospital NHS Trust, London WC1N 1EH, UK
- Adrian J. Thrasher
- Molecular and Cellular Immunology, Great Ormond Street Institute of Child Health, and Great Ormond Street Hospital NHS Trust, London WC1N 1EH, UK
- Daniela Salvatori
- Central Laboratory Animal Facility, Pathology Unit, Leiden University Medical Center, 2333ZA Leiden, the Netherlands; Department of Pharmacy, Leiden University Medical Center, 2333ZA Leiden, the Netherlands; Pathogenesis and Treatment of Immune and Bone Diseases Unit, San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy; Anatomy and Physiology Division, Clinical Sciences, Faculty of Veterinary Medicine, Utrecht University, Yalelaan1, 3584CL Utrecht, the Netherlands
- Pauline Meij
- Department of Pharmacy, Leiden University Medical Center, 2333ZA Leiden, the Netherlands
- Anna Villa
- Pathogenesis and Treatment of Immune and Bone Diseases Unit, San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
- Jacques J.M. Van Dongen
- Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2333ZA Leiden, the Netherlands
- Jaap-Jan Zwaginga
- Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2333ZA Leiden, the Netherlands
- Mirjam van der Burg
- Willem-Alexander Children’s Hospital Department of Pediatrics, Leiden University Medical Center, 2333ZA Leiden, the Netherlands
- H. Bobby Gaspar
- Molecular and Cellular Immunology, Great Ormond Street Institute of Child Health, and Great Ormond Street Hospital NHS Trust, London WC1N 1EH, UK
- Arjan Lankester
- Willem-Alexander Children’s Hospital Department of Pediatrics, Leiden University Medical Center, 2333ZA Leiden, the Netherlands
- Frank J.T. Staal
- Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2333ZA Leiden, the Netherlands; Corresponding author: Frank J.T. Staal, Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2333ZA Leiden, the Netherlands.
- Karin Pike-Overzet
- Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2333ZA Leiden, the Netherlands
- Journal volume & issue
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Vol. 17
pp. 666 – 682
Abstract
Recombinase-activating gene-1 (RAG1)-deficient severe combined immunodeficiency (SCID) patients lack B and T lymphocytes due to the inability to rearrange immunoglobulin and T cell receptor genes. Gene therapy is an alternative for those RAG1-SCID patients who lack a suitable bone marrow donor. We designed lentiviral vectors with different internal promoters driving codon-optimized RAG1 to ensure optimal expression. We used Rag1−/− mice as a preclinical model for RAG1-SCID to assess the efficacy of the various vectors. We observed that B and T cell reconstitution directly correlated with RAG1 expression. Mice with low RAG1 expression showed poor immune reconstitution; however, higher expression resulted in phenotypic and functional lymphocyte reconstitution comparable to mice receiving wild-type stem cells. No signs of genotoxicity were found. Additionally, RAG1-SCID patient CD34+ cells transduced with our clinical RAG1 vector and transplanted into NSG mice led to improved human B and T cell development. Considering this efficacy outcome, together with favorable safety data, these results substantiate the need for a clinical trial for RAG1-SCID.
