Restoration of T and B Cell Differentiation after RAG1 Gene Transfer in Human RAG1 Defective Hematopoietic Stem Cells.

Autor:	Sorel N; Human Lymphohematopoiesis Laboratory, Université Paris Cité, Imagine Institute, INSERM UMR 1163, 75015 Paris, France., Díaz-Pascual F; ProtaGene CGT GmbH, Im Neuenheimer Feld 582, 69120 Heidelberg, Germany., Bessot B; Biotherapy Clinical Investigation Center, Groupe Hospitalier Universitaire Ouest, AP-HP, INSERM, 75015 Paris, France., Sadek H; Human Lymphohematopoiesis Laboratory, Université Paris Cité, Imagine Institute, INSERM UMR 1163, 75015 Paris, France., Mollet C; Biotherapy Clinical Investigation Center, Groupe Hospitalier Universitaire Ouest, AP-HP, INSERM, 75015 Paris, France., Chouteau M; Human Lymphohematopoiesis Laboratory, Université Paris Cité, Imagine Institute, INSERM UMR 1163, 75015 Paris, France., Zahn M; ProtaGene CGT GmbH, Im Neuenheimer Feld 582, 69120 Heidelberg, Germany., Gil-Farina I; ProtaGene CGT GmbH, Im Neuenheimer Feld 582, 69120 Heidelberg, Germany., Tajer P; Department of Immunohematology and Blood Transfusion, L3-Q Leiden University Medical Center, 2333 ZA Leiden, The Netherlands., van Eggermond M; Department of Immunohematology and Blood Transfusion, L3-Q Leiden University Medical Center, 2333 ZA Leiden, The Netherlands., Berghuis D; Department of Pediatrics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands., Lankester AC; Department of Pediatrics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands., André I; Human Lymphohematopoiesis Laboratory, Université Paris Cité, Imagine Institute, INSERM UMR 1163, 75015 Paris, France., Gabriel R; ProtaGene CGT GmbH, Im Neuenheimer Feld 582, 69120 Heidelberg, Germany., Cavazzana M; Biotherapy Clinical Investigation Center, Groupe Hospitalier Universitaire Ouest, AP-HP, INSERM, 75015 Paris, France.; Biotherapy Department, Necker-Enfants Malades Hospital, AP-HP, 75015 Paris, France.; Imagine Institute UMR1163, Université Paris Cité, Sorbonne Paris Cité, 75015 Paris, France., Pike-Overzet K; Biotherapy Department, Necker-Enfants Malades Hospital, AP-HP, 75015 Paris, France., Staal FJT; Department of Immunohematology and Blood Transfusion, L3-Q Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.; Department of Pediatrics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands., Lagresle-Peyrou C; Human Lymphohematopoiesis Laboratory, Université Paris Cité, Imagine Institute, INSERM UMR 1163, 75015 Paris, France.; Biotherapy Clinical Investigation Center, Groupe Hospitalier Universitaire Ouest, AP-HP, INSERM, 75015 Paris, France.
Jazyk:	angličtina
Zdroj:	Biomedicines [Biomedicines] 2024 Jul 05; Vol. 12 (7). Date of Electronic Publication: 2024 Jul 05.
DOI:	10.3390/biomedicines12071495
Abstrakt:	Recombinase-activating gene (RAG)-deficient SCID patients lack B and T lymphocytes due to the inability to rearrange immunoglobulin and T cell receptor genes. The two RAG genes act as a required dimer to initiate gene recombination. Gene therapy is a valid treatment alternative for RAG-SCID patients who lack a suitable bone marrow donor, but developing such therapy for RAG1/2 has proven challenging. Using a clinically approved lentiviral vector with a codon-optimized RAG1 gene, we report here preclinical studies using CD34+ cells from four RAG1-SCID patients. We used in vitro T cell developmental assays and in vivo assays in xenografted NSG mice. The RAG1-SCID patient CD34 + cells transduced with the RAG1 vector and transplanted into NSG mice led to restored human B and T cell development. Together with favorable safety data on integration sites, these results substantiate an ongoing phase I/II clinical trial for RAG1-SCID. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial purposes that could be considered as a potential conflict of interest. F.D.-P., M.Z., I.G.-F. and R.G. were full-time employees at ProtaGene CGT GbmH at the time when the work was performed.
Databáze:	MEDLINE
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