Successful Preclinical Development of Gene Therapy for Recombinase-Activating Gene-1-Deficient SCID
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 d...
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| Format: | Article |
| Language: | English |
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Elsevier
2020-06-01
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| Series: | Molecular Therapy: Methods & Clinical Development |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2329050120300462 |
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Article |
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DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
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 |
| spellingShingle |
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 Successful Preclinical Development of Gene Therapy for Recombinase-Activating Gene-1-Deficient SCID Molecular Therapy: Methods & Clinical Development gene therapy SCID B lymphocytes T lymphocytes CD34+ cells gene rearrangement |
| author_facet |
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 |
| author_sort |
Laura Garcia-Perez |
| title |
Successful Preclinical Development of Gene Therapy for Recombinase-Activating Gene-1-Deficient SCID |
| title_short |
Successful Preclinical Development of Gene Therapy for Recombinase-Activating Gene-1-Deficient SCID |
| title_full |
Successful Preclinical Development of Gene Therapy for Recombinase-Activating Gene-1-Deficient SCID |
| title_fullStr |
Successful Preclinical Development of Gene Therapy for Recombinase-Activating Gene-1-Deficient SCID |
| title_full_unstemmed |
Successful Preclinical Development of Gene Therapy for Recombinase-Activating Gene-1-Deficient SCID |
| title_sort |
successful preclinical development of gene therapy for recombinase-activating gene-1-deficient scid |
| publisher |
Elsevier |
| series |
Molecular Therapy: Methods & Clinical Development |
| issn |
2329-0501 |
| publishDate |
2020-06-01 |
| description |
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. |
| topic |
gene therapy SCID B lymphocytes T lymphocytes CD34+ cells gene rearrangement |
| url |
http://www.sciencedirect.com/science/article/pii/S2329050120300462 |
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doaj-054d2c31c1974fd68ef81093f23e0c9c2020-11-25T03:26:01ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012020-06-0117666682Successful Preclinical Development of Gene Therapy for Recombinase-Activating Gene-1-Deficient SCIDLaura Garcia-Perez0Marja van Eggermond1Lieke van Roon2Sandra A. Vloemans3Martijn Cordes4Axel Schambach5Michael Rothe6Dagmar Berghuis7Chantal Lagresle-Peyrou8Marina Cavazzana9Fang Zhang10Adrian J. Thrasher11Daniela Salvatori12Pauline Meij13Anna Villa14Jacques J.M. Van Dongen15Jaap-Jan Zwaginga16Mirjam van der Burg17H. Bobby Gaspar18Arjan Lankester19Frank J.T. Staal20Karin Pike-Overzet21Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2333ZA Leiden, the NetherlandsDepartment of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2333ZA Leiden, the NetherlandsDepartment of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2333ZA Leiden, the NetherlandsDepartment of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2333ZA Leiden, the NetherlandsDepartment of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2333ZA Leiden, the NetherlandsInstitute of Experimental Hematology, Hannover Medical School, 30625 Hannover, GermanyInstitute of Experimental Hematology, Hannover Medical School, 30625 Hannover, GermanyWillem-Alexander Children’s Hospital Department of Pediatrics, Leiden University Medical Center, 2333ZA Leiden, the NetherlandsBiotherapy 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, FranceBiotherapy 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, FranceMolecular and Cellular Immunology, Great Ormond Street Institute of Child Health, and Great Ormond Street Hospital NHS Trust, London WC1N 1EH, UKMolecular and Cellular Immunology, Great Ormond Street Institute of Child Health, and Great Ormond Street Hospital NHS Trust, London WC1N 1EH, UKCentral 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 NetherlandsDepartment of Pharmacy, Leiden University Medical Center, 2333ZA Leiden, the NetherlandsPathogenesis and Treatment of Immune and Bone Diseases Unit, San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, 20132 Milan, ItalyDepartment of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2333ZA Leiden, the NetherlandsDepartment of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2333ZA Leiden, the NetherlandsWillem-Alexander Children’s Hospital Department of Pediatrics, Leiden University Medical Center, 2333ZA Leiden, the NetherlandsMolecular and Cellular Immunology, Great Ormond Street Institute of Child Health, and Great Ormond Street Hospital NHS Trust, London WC1N 1EH, UKWillem-Alexander Children’s Hospital Department of Pediatrics, Leiden University Medical Center, 2333ZA Leiden, the NetherlandsDepartment 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.Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2333ZA Leiden, the NetherlandsRecombinase-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.http://www.sciencedirect.com/science/article/pii/S2329050120300462gene therapySCIDB lymphocytesT lymphocytesCD34+ cellsgene rearrangement |