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Genetically corrected RAG2-SCID human hematopoietic stem cells restore V(D)J-recombinase and rescue lymphoid deficiency.
Pavel-Dinu, Mara; Gardner, Cameron L; Nakauchi, Yusuke; Kawai, Tomoki; Delmonte, Ottavia M; Palterer, Boaz; Bosticardo, Marita; Pala, Francesca; Viel, Sebastien; Malech, Harry L; Ghanim, Hana Y; Bode, Nicole M; Kurgan, Gavin L; Detweiler, Angela M; Vakulskas, Christopher A; Neff, Norma F; Sheikali, Adam; Menezes, Sherah T; Chrobok, Jade; Hernández González, Elaine M; Majeti, Ravindra; Notarangelo, Luigi D; Porteus, Matthew H.
Afiliación
  • Pavel-Dinu M; Division of Oncology, Hematology, Stem Cell Transplantation, Department of Pediatrics, Stanford University, Stanford, CA.
  • Gardner CL; Immune Deficiency Genetics Section, Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
  • Nakauchi Y; Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom.
  • Kawai T; Division of Hematology, Department of Medicine, Cancer Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA.
  • Delmonte OM; Immune Deficiency Genetics Section, Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
  • Palterer B; Immune Deficiency Genetics Section, Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
  • Bosticardo M; Immune Deficiency Genetics Section, Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
  • Pala F; Immune Deficiency Genetics Section, Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
  • Viel S; Immune Deficiency Genetics Section, Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
  • Malech HL; Division of Oncology, Hematology, Stem Cell Transplantation, Department of Pediatrics, Stanford University, Stanford, CA.
  • Ghanim HY; Service d'immunologie biologique, Hospices Civils de Lyon, Centre International de Recherche en Infectivologie, Centre International de Recheerche in Infectivalogie, INSERM U1111, Université Claude Bernard Lyon 1, Centre National de la Recherge Scientifique, UMR5308, École Normale Supérieure de Lyon
  • Bode NM; Genetic Immunotherapy Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
  • Kurgan GL; Division of Oncology, Hematology, Stem Cell Transplantation, Department of Pediatrics, Stanford University, Stanford, CA.
  • Detweiler AM; Integrated DNA Technologies, Inc, Coralville, IA.
  • Vakulskas CA; Integrated DNA Technologies, Inc, Coralville, IA.
  • Neff NF; Chan Zuckerberg Biohub, San Francisco, CA.
  • Sheikali A; Integrated DNA Technologies, Inc, Coralville, IA.
  • Menezes ST; Chan Zuckerberg Biohub, San Francisco, CA.
  • Chrobok J; Division of Oncology, Hematology, Stem Cell Transplantation, Department of Pediatrics, Stanford University, Stanford, CA.
  • Hernández González EM; Division of Oncology, Hematology, Stem Cell Transplantation, Department of Pediatrics, Stanford University, Stanford, CA.
  • Majeti R; Division of Oncology, Hematology, Stem Cell Transplantation, Department of Pediatrics, Stanford University, Stanford, CA.
  • Notarangelo LD; Division of Oncology, Hematology, Stem Cell Transplantation, Department of Pediatrics, Stanford University, Stanford, CA.
  • Porteus MH; Division of Hematology, Department of Medicine, Cancer Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA.
Blood Adv ; 8(7): 1820-1833, 2024 Apr 09.
Article en En | MEDLINE | ID: mdl-38096800
ABSTRACT
ABSTRACT Recombination-activating genes (RAG1 and RAG2) are critical for lymphoid cell development and function by initiating the variable (V), diversity (D), and joining (J) (V(D)J)-recombination process to generate polyclonal lymphocytes with broad antigen specificity. The clinical manifestations of defective RAG1/2 genes range from immune dysregulation to severe combined immunodeficiencies (SCIDs), causing life-threatening infections and death early in life without hematopoietic cell transplantation (HCT). Despite improvements, haploidentical HCT without myeloablative conditioning carries a high risk of graft failure and incomplete immune reconstitution. The RAG complex is only expressed during the G0-G1 phase of the cell cycle in the early stages of T- and B-cell development, underscoring that a direct gene correction might capture the precise temporal expression of the endogenous gene. Here, we report a feasibility study using the CRISPR/Cas9-based "universal gene-correction" approach for the RAG2 locus in human hematopoietic stem/progenitor cells (HSPCs) from healthy donors and RAG2-SCID patient. V(D)J-recombinase activity was restored after gene correction of RAG2-SCID-derived HSPCs, resulting in the development of T-cell receptor (TCR) αß and γδ CD3+ cells and single-positive CD4+ and CD8+ lymphocytes. TCR repertoire analysis indicated a normal distribution of CDR3 length and preserved usage of the distal TRAV genes. We confirmed the in vivo rescue of B-cell development with normal immunoglobulin M surface expression and a significant decrease in CD56bright natural killer cells. Together, we provide specificity, toxicity, and efficacy data supporting the development of a gene-correction therapy to benefit RAG2-deficient patients.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Inmunodeficiencia Combinada Grave / Proteínas de Homeodominio Límite: Humans Idioma: En Revista: Blood Adv Año: 2024 Tipo del documento: Article País de afiliación: Canadá Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Inmunodeficiencia Combinada Grave / Proteínas de Homeodominio Límite: Humans Idioma: En Revista: Blood Adv Año: 2024 Tipo del documento: Article País de afiliación: Canadá Pais de publicación: Estados Unidos