17 results on '"X-Linked Combined Immunodeficiency Diseases therapy"'
Search Results
2. Elucidation of the Effects of a Current X-SCID Therapy on Intestinal Lymphoid Organogenesis Using an In Vivo Animal Model.
- Author
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Nochi T, Suzuki S, Ito S, Morita S, Furukawa M, Fuchimoto D, Sasahara Y, Usami K, Niimi K, Itano O, Kitago M, Matsuda S, Matsuo A, Suyama Y, Sakai Y, Wu G, Bazer FW, Watanabe K, Onishi A, and Aso H
- Subjects
- Adolescent, Adult, Animals, Animals, Genetically Modified, Child, Child, Preschool, Disease Models, Animal, Female, Gastrointestinal Microbiome immunology, Gene Knockout Techniques, Humans, Immunity, Mucosal, Immunoglobulin G blood, Immunoglobulin G immunology, Intestinal Mucosa immunology, Intestinal Mucosa microbiology, Male, Organogenesis genetics, Organogenesis immunology, Peyer's Patches immunology, Swine, Treatment Outcome, X-Linked Combined Immunodeficiency Diseases genetics, X-Linked Combined Immunodeficiency Diseases immunology, X-Linked Combined Immunodeficiency Diseases pathology, Bone Marrow Transplantation, Interleukin Receptor Common gamma Subunit genetics, Intestinal Mucosa growth & development, Peyer's Patches growth & development, X-Linked Combined Immunodeficiency Diseases therapy
- Abstract
Background & Aims: Organ-level research using an animal model lacking Il2rg, the gene responsible for X-linked severe combined immunodeficiency (X-SCID), is clinically unavailable and would be a powerful tool to gain deeper insights into the symptoms of patients with X-SCID., Methods: We used an X-SCID animal model, which was first established in our group by the deletion of Il2rg gene in pigs, to understand the clinical signs from multiple perspectives based on pathology, immunology, microbiology, and nutrition. We also treated the X-SCID pigs with bone marrow transplantation (BMT) for mimicking a current therapeutic treatment for patients with X-SCID and investigated the effect at the organ-level. Moreover, the results were confirmed using serum and fecal samples collected from patients with X-SCID., Results: We demonstrated that X-SCID pigs completely lacked Peyer's patches (PPs) and IgA production in the small intestine, but possessed some dysfunctional intestinal T and B cells. Another novel discovery was that X-SCID pigs developed a heterogeneous intestinal microflora and possessed abnormal plasma metabolites, indicating that X-SCID could be an immune disorder that affects various in vivo functions. Importantly, the organogenesis of PPs in X-SCID pigs was not promoted by BMT. Although a few isolated lymphoid follicles developed in the small intestine of BMT-treated X-SCID pigs, there was no evidence that they contributed to IgA production and microflora formation. Consistently, most patients with X-SCID who received BMT possessed abnormal intestinal immune and microbial environments regardless of the presence of sufficient serum IgG., Conclusions: These results indicate that the current BMT therapies for patients with X-SCID may be insufficient to induce the organogenesis of intestinal lymphoid tissues that are associated with numerous functions in vivo., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2020
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3. New Gene Therapy Potential Cure for "Bubble Boy Disease": An experimental gene therapy has allowed children with SCID-1X to develop fully functioning immune systems.
- Subjects
- Busulfan therapeutic use, Child, Child, Preschool, Female, Gene Expression, Genetic Vectors chemistry, Genetic Vectors metabolism, Humans, Immune System drug effects, Immune System immunology, Immune System pathology, Immunosuppressive Agents therapeutic use, Infant, Interleukin Receptor Common gamma Subunit deficiency, Interleukin Receptor Common gamma Subunit immunology, Lentivirus metabolism, Male, T-Lymphocytes drug effects, T-Lymphocytes immunology, T-Lymphocytes pathology, X-Linked Combined Immunodeficiency Diseases genetics, X-Linked Combined Immunodeficiency Diseases immunology, X-Linked Combined Immunodeficiency Diseases pathology, Genetic Therapy methods, Interleukin Receptor Common gamma Subunit genetics, Lentivirus genetics, Therapies, Investigational methods, X-Linked Combined Immunodeficiency Diseases therapy
- Published
- 2019
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4. Lentiviral Gene Therapy Combined with Low-Dose Busulfan in Infants with SCID-X1.
- Author
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Mamcarz E, Zhou S, Lockey T, Abdelsamed H, Cross SJ, Kang G, Ma Z, Condori J, Dowdy J, Triplett B, Li C, Maron G, Aldave Becerra JC, Church JA, Dokmeci E, Love JT, da Matta Ain AC, van der Watt H, Tang X, Janssen W, Ryu BY, De Ravin SS, Weiss MJ, Youngblood B, Long-Boyle JR, Gottschalk S, Meagher MM, Malech HL, Puck JM, Cowan MJ, and Sorrentino BP
- Subjects
- Antigens, Differentiation, T-Lymphocyte blood, B-Lymphocytes physiology, Hematopoietic Stem Cell Transplantation, Humans, Immunoglobulin M blood, Infant, Killer Cells, Natural, Lymphocyte Count, Male, T-Lymphocytes, X-Linked Combined Immunodeficiency Diseases genetics, X-Linked Combined Immunodeficiency Diseases immunology, Busulfan administration & dosage, Genetic Therapy, Genetic Vectors, Interleukin Receptor Common gamma Subunit genetics, Lentivirus, Transplantation Conditioning, X-Linked Combined Immunodeficiency Diseases therapy
- Abstract
Background: Allogeneic hematopoietic stem-cell transplantation for X-linked severe combined immunodeficiency (SCID-X1) often fails to reconstitute immunity associated with T cells, B cells, and natural killer (NK) cells when matched sibling donors are unavailable unless high-dose chemotherapy is given. In previous studies, autologous gene therapy with γ-retroviral vectors failed to reconstitute B-cell and NK-cell immunity and was complicated by vector-related leukemia., Methods: We performed a dual-center, phase 1-2 safety and efficacy study of a lentiviral vector to transfer IL2RG complementary DNA to bone marrow stem cells after low-exposure, targeted busulfan conditioning in eight infants with newly diagnosed SCID-X1., Results: Eight infants with SCID-X1 were followed for a median of 16.4 months. Bone marrow harvest, busulfan conditioning, and cell infusion had no unexpected side effects. In seven infants, the numbers of CD3+, CD4+, and naive CD4+ T cells and NK cells normalized by 3 to 4 months after infusion and were accompanied by vector marking in T cells, B cells, NK cells, myeloid cells, and bone marrow progenitors. The eighth infant had an insufficient T-cell count initially, but T cells developed in this infant after a boost of gene-corrected cells without busulfan conditioning. Previous infections cleared in all infants, and all continued to grow normally. IgM levels normalized in seven of the eight infants, of whom four discontinued intravenous immune globulin supplementation; three of these four infants had a response to vaccines. Vector insertion-site analysis was performed in seven infants and showed polyclonal patterns without clonal dominance in all seven., Conclusions: Lentiviral vector gene therapy combined with low-exposure, targeted busulfan conditioning in infants with newly diagnosed SCID-X1 had low-grade acute toxic effects and resulted in multilineage engraftment of transduced cells, reconstitution of functional T cells and B cells, and normalization of NK-cell counts during a median follow-up of 16 months. (Funded by the American Lebanese Syrian Associated Charities and others; LVXSCID-ND ClinicalTrials.gov number, NCT01512888.)., (Copyright © 2019 Massachusetts Medical Society.)
- Published
- 2019
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5. The γ c Family of Cytokines: Basic Biology to Therapeutic Ramifications.
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Leonard WJ, Lin JX, and O'Shea JJ
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- Animals, Autoimmune Diseases genetics, Autoimmune Diseases immunology, Cytokines genetics, Cytokines immunology, Evolution, Molecular, Gene Expression Regulation, Genetic Therapy, Humans, Immunologic Deficiency Syndromes immunology, Immunologic Deficiency Syndromes therapy, Janus Kinase 3 antagonists & inhibitors, Janus Kinases antagonists & inhibitors, Janus Kinases physiology, Lymphocyte Subsets immunology, Mice, Molecular Targeted Therapy, Multigene Family genetics, Neoplasms genetics, Neoplasms immunology, Protein Subunits, STAT Transcription Factors physiology, Signal Transduction, Translational Research, Biomedical, X-Linked Combined Immunodeficiency Diseases genetics, X-Linked Combined Immunodeficiency Diseases immunology, X-Linked Combined Immunodeficiency Diseases therapy, Cytokines classification, Interleukin Receptor Common gamma Subunit genetics, Multigene Family immunology
- Abstract
The common cytokine receptor γ chain, γ
c , is a component of the receptors for interleukin-2 (IL-2), IL-4, IL-7, IL-9, IL-15, and IL-21. Mutation of the gene encoding γc results in X-linked severe combined immunodeficiency in humans, and γc family cytokines collectively regulate development, proliferation, survival, and differentiation of immune cells. Here, we review the basic biology of these cytokines, highlighting mechanisms of signaling and gene regulation that have provided insights for immunodeficiency, autoimmunity, allergic diseases, and cancer. Moreover, we discuss how studies of this family stimulated the development of JAK3 inhibitors and present an overview of current strategies targeting these pathways in the clinic, including novel antibodies, antagonists, and partial agonists. The diverse roles of these cytokines on a range of immune cells have important therapeutic implications., (Copyright © 2019. Published by Elsevier Inc.)- Published
- 2019
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6. Gene correction for SCID-X1 in long-term hematopoietic stem cells.
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Pavel-Dinu M, Wiebking V, Dejene BT, Srifa W, Mantri S, Nicolas CE, Lee C, Bao G, Kildebeck EJ, Punjya N, Sindhu C, Inlay MA, Saxena N, DeRavin SS, Malech H, Roncarolo MG, Weinberg KI, and Porteus MH
- Subjects
- Animals, Antigens, CD34 metabolism, CRISPR-Cas Systems genetics, Cell Line, Codon, Initiator genetics, Dependovirus, Exons genetics, Fetal Blood cytology, Genetic Vectors genetics, Healthy Volunteers, Hematopoietic Stem Cells metabolism, Humans, Male, Mice, Mutation, Parvovirinae genetics, Primary Cell Culture, Time Factors, Transduction, Genetic methods, Transplantation Chimera genetics, Transplantation, Heterologous methods, X-Linked Combined Immunodeficiency Diseases genetics, DNA, Complementary genetics, Gene Editing methods, Hematopoietic Stem Cell Transplantation, Interleukin Receptor Common gamma Subunit genetics, X-Linked Combined Immunodeficiency Diseases therapy
- Abstract
Gene correction in human long-term hematopoietic stem cells (LT-HSCs) could be an effective therapy for monogenic diseases of the blood and immune system. Here we describe an approach for X-linked sSevere cCombined iImmunodeficiency (SCID-X1) using targeted integration of a cDNA into the endogenous start codon to functionally correct disease-causing mutations throughout the gene. Using a CRISPR-Cas9/AAV6 based strategy, we achieve up to 20% targeted integration frequencies in LT-HSCs. As measures of the lack of toxicity we observe no evidence of abnormal hematopoiesis following transplantation and no evidence of off-target mutations using a high-fidelity Cas9 as a ribonucleoprotein complex. We achieve high levels of targeting frequencies (median 45%) in CD34
+ HSPCs from six SCID-X1 patients and demonstrate rescue of lymphopoietic defect in a patient derived HSPC population in vitro and in vivo. In sum, our study provides specificity, toxicity and efficacy data supportive of clinical development of genome editing to treat SCID-Xl.- Published
- 2019
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7. Nuclease-free Adeno-Associated Virus-Mediated Il2rg Gene Editing in X-SCID Mice.
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Hiramoto T, Li LB, Funk SE, Hirata RK, and Russell DW
- Subjects
- Alleles, Animals, Bone Marrow Cells immunology, Bone Marrow Cells metabolism, Gene Order, Genetic Therapy, Hematopoietic Stem Cells metabolism, Humans, Immunotherapy, Adoptive, Mice, Receptors, Antigen, T-Cell metabolism, T-Lymphocytes immunology, T-Lymphocytes metabolism, X-Linked Combined Immunodeficiency Diseases immunology, X-Linked Combined Immunodeficiency Diseases therapy, Dependovirus genetics, Gene Editing, Genetic Vectors genetics, Interleukin Receptor Common gamma Subunit genetics, X-Linked Combined Immunodeficiency Diseases genetics
- Abstract
X-linked severe combined immunodeficiency (X-SCID) has been successfully treated by hematopoietic stem cell (HSC) transduction with retroviral vectors expressing the interleukin-2 receptor subunit gamma gene (IL2RG), but several patients developed malignancies due to vector integration near cellular oncogenes. This adverse side effect could in principle be avoided by accurate IL2RG gene editing with a vector that does not contain a functional promoter or IL2RG gene. Here, we show that adeno-associated virus (AAV) gene editing vectors can insert a partial Il2rg cDNA at the endogenous Il2rg locus in X-SCID murine bone marrow cells and that these ex vivo-edited cells repopulate transplant recipients and produce CD4
+ and CD8+ T cells. Circulating, edited lymphocytes increased over time and appeared in secondary transplant recipients, demonstrating successful editing in long-term repopulating cells. Random vector integration events were nearly undetectable, and malignant transformation of the transplanted cells was not observed. Similar editing frequencies were observed in human hematopoietic cells. Our results demonstrate that therapeutically relevant HSC gene editing can be achieved by AAV vectors in the absence of site-specific nucleases and suggest that this may be a safe and effective therapy for hematopoietic diseases where in vivo selection can increase edited cell numbers., (Copyright © 2018 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)- Published
- 2018
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8. Targeted genome editing restores T cell differentiation in a humanized X-SCID pluripotent stem cell disease model.
- Author
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Alzubi J, Pallant C, Mussolino C, Howe SJ, Thrasher AJ, and Cathomen T
- Subjects
- Amino Acid Substitution, Animals, Cell Differentiation, Disease Models, Animal, Gene Expression, Hematopoietic Stem Cells drug effects, Hematopoietic Stem Cells pathology, Humans, Interleukin Receptor Common gamma Subunit deficiency, Interleukin Receptor Common gamma Subunit immunology, Interleukin-2 genetics, Interleukin-2 immunology, Interleukin-2 pharmacology, Interleukin-7 genetics, Interleukin-7 immunology, Interleukin-7 pharmacology, Killer Cells, Natural drug effects, Killer Cells, Natural immunology, Killer Cells, Natural pathology, Mice, Mice, SCID, Mice, Transgenic, Molecular Targeted Therapy, Mouse Embryonic Stem Cells drug effects, Mouse Embryonic Stem Cells pathology, Mutation, T-Lymphocytes drug effects, T-Lymphocytes immunology, T-Lymphocytes pathology, Transcription Activator-Like Effector Nucleases genetics, Transcription Activator-Like Effector Nucleases immunology, Transgenes, X-Linked Combined Immunodeficiency Diseases immunology, X-Linked Combined Immunodeficiency Diseases pathology, Gene Editing methods, Hematopoietic Stem Cells immunology, Interleukin Receptor Common gamma Subunit genetics, Mouse Embryonic Stem Cells immunology, X-Linked Combined Immunodeficiency Diseases genetics, X-Linked Combined Immunodeficiency Diseases therapy
- Abstract
The generation of T cells from pluripotent stem cells (PSCs) is attractive for investigating T cell development and validating genome editing strategies in vitro. X-linked severe combined immunodeficiency (X-SCID) is an immune disorder caused by mutations in the IL2RG gene and characterised by the absence of T and NK cells in patients. IL2RG encodes the common gamma chain, which is part of several interleukin receptors, including IL-2 and IL-7 receptors. To model X-SCID in vitro, we generated a mouse embryonic stem cell (ESC) line in which a disease-causing human IL2RG gene variant replaces the endogenous Il2rg locus. We developed a stage-specific T cell differentiation protocol to validate genetic correction of the common G691A mutation with transcription activator-like effector nucleases. While all ESC clones could be differentiated to hematopoietic precursor cells, stage-specific analysis of T cell maturation confirmed early arrest of T cell differentiation at the T cell progenitor stage in X-SCID cells. In contrast, genetically corrected ESCs differentiated to CD4 + or CD8 + single-positive T cells, confirming correction of the cellular X-SCID phenotype. This study emphasises the value of PSCs for disease modelling and underlines the significance of in vitro models as tools to validate genome editing strategies before clinical application.
- Published
- 2017
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9. Faster T-cell development following gene therapy compared with haploidentical HSCT in the treatment of SCID-X1.
- Author
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Touzot F, Moshous D, Creidy R, Neven B, Frange P, Cros G, Caccavelli L, Blondeau J, Magnani A, Luby JM, Ternaux B, Picard C, Blanche S, Fischer A, Hacein-Bey-Abina S, and Cavazzana M
- Subjects
- Adolescent, Allografts, Child, Child, Preschool, Female, Graft vs Host Disease etiology, Graft vs Host Disease genetics, Graft vs Host Disease immunology, Graft vs Host Disease pathology, Humans, Infant, Interleukin Receptor Common gamma Subunit genetics, Male, Mutation, Prospective Studies, Retrospective Studies, T-Lymphocytes pathology, Thymus Gland pathology, X-Linked Combined Immunodeficiency Diseases genetics, X-Linked Combined Immunodeficiency Diseases immunology, X-Linked Combined Immunodeficiency Diseases pathology, Genetic Therapy, Hematopoietic Stem Cell Transplantation, Interleukin Receptor Common gamma Subunit immunology, T-Lymphocytes immunology, Thymus Gland immunology, X-Linked Combined Immunodeficiency Diseases therapy
- Abstract
During the last decade, gene therapy via ex vivo gene transfer into autologous hematopoietic stem cells has emerged as a convincing therapy for severe combined immunodeficiency caused by ILR2G mutation (SCID-X1) despite the occurrence of genotoxicity caused by the integration of first-generation retroviral vectors. However, the place of gene therapy among the therapeutic armamentarium remains to be defined. We retrospectively analyze and compare clinical outcomes and immune reconstitution in 13 consecutive SCID-X1 patients having undergone haploidentical hematopoietic stem cell transplantation (HSCT) and 14 SCID-X1 patients treated with gene therapy over the same period at a single center level: the Necker Children's Hospital (Paris, France). Our results show a clear advantage in terms of T-cell development of gene therapy over HSCT with a mismatched donor. Patients treated with gene therapy display a faster T-cell reconstitution and a better long-term thymic output. Interestingly, this advantage of gene therapy vs haploidentical HSCT seems to be independent of the existence of clinical graft-versus-host disease in the latter condition. If data of safety are confirmed over the long term, gene therapy for SCID-X1 appears to be an equal, if not superior, alternative to haploidentical HSCT., (© 2015 by The American Society of Hematology.)
- Published
- 2015
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10. Gene therapy outpaces haplo for SCID-X1.
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Kohn DB
- Subjects
- Female, Humans, Male, Genetic Therapy, Hematopoietic Stem Cell Transplantation, Interleukin Receptor Common gamma Subunit immunology, T-Lymphocytes immunology, Thymus Gland immunology, X-Linked Combined Immunodeficiency Diseases therapy
- Abstract
In this issue of Blood, Touzot et al report that autologous gene therapy/hematopoietic stem cell transplantation (HSCT) for infants with X-linked severe combined immune deficiency (SCID-X1) lacking a matched sibling donor may have better outcomes than haploidentical (haplo) HSCT. Because gene therapy represents an autologous transplant, it obviates immune suppression before and after transplant, eliminates risks of graft versus host disease (GVHD), and, as the authors report, led to faster immunological reconstitution after transplant than did haplo transplant.
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- 2015
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11. Critical variables affecting clinical-grade production of the self-inactivating gamma-retroviral vector for the treatment of X-linked severe combined immunodeficiency.
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van der Loo JC, Swaney WP, Grassman E, Terwilliger A, Higashimoto T, Schambach A, Hacein-Bey-Abina S, Nordling DL, Cavazzana-Calvo M, Thrasher AJ, Williams DA, Reeves L, and Malik P
- Subjects
- Animals, Gene Transfer Techniques, Humans, Leukemia Virus, Gibbon Ape genetics, Mice, Mice, Inbred NOD, Mice, SCID, Terminal Repeat Sequences, Transduction, Genetic, Genetic Vectors, Interleukin Receptor Common gamma Subunit genetics, Retroviridae genetics, X-Linked Combined Immunodeficiency Diseases therapy
- Abstract
Patients with X-linked severe combined immunodeficiency (SCID-X1) were successfully cured following gene therapy with a gamma-retroviral vector (gRV) expressing the common gamma chain of the interleukin-2 receptor (IL2RG). However, 5 of 20 patients developed leukemia from activation of cellular proto-oncogenes by viral enhancers in the long-terminal repeats (LTR) of the integrated vector. These events prompted the design of a gRV vector with self-inactivating (SIN) LTRs to enhance vector safety. Herein we report on the production of a clinical-grade SIN IL2RG gRV pseudotyped with the Gibbon Ape Leukemia Virus envelope for a new gene therapy trial for SCID-X1, and highlight variables that were found to be critical for transfection-based large-scale SIN gRV production. Successful clinical production required careful selection of culture medium without pre-added glutamine, reduced exposure of packaging cells to cell-dissociation enzyme, and presence of cations in wash buffer. The clinical vector was high titer; transduced 68-70% normal human CD34(+) cells, as determined by colony-forming unit assays and by xenotransplantation in immunodeficient NOD.CB17-Prkdc(scid)/J (nonobese diabetic/severe combined immunodeficiency (NOD/SCID)) and NOD.Cg-Prkdc(scid) Il2rg(tm1Wjl)/SzJ (NOD/SCID gamma (NSG))) mice; and resulted in the production of T cells in vitro from human SCID-X1 CD34(+) cells. The vector was certified and released for the treatment of SCID-X1 in a multi-center international phase I/II trial.
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- 2012
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12. Gene therapy for SCID-X1: focus on clinical data.
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Baum C
- Subjects
- Clinical Trials as Topic, Humans, Genetic Therapy, Interleukin Receptor Common gamma Subunit genetics, X-Linked Combined Immunodeficiency Diseases genetics, X-Linked Combined Immunodeficiency Diseases therapy
- Published
- 2011
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13. Correction of SCID-X1 using an enhancerless Vav promoter.
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Almarza E, Zhang F, Santilli G, Blundell MP, Howe SJ, Thornhill SI, Bueren JA, and Thrasher AJ
- Subjects
- Animals, Base Sequence, Cell Line, Tumor, Disease Models, Animal, Gene Expression Regulation genetics, Gene Order, Genetic Vectors genetics, HEK293 Cells, Hematopoietic Stem Cell Transplantation, Hematopoietic Stem Cells metabolism, Humans, Interleukin Receptor Common gamma Subunit metabolism, Interleukin-2 metabolism, Lentivirus genetics, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Molecular Sequence Data, Signal Transduction, X-Linked Combined Immunodeficiency Diseases genetics, X-Linked Combined Immunodeficiency Diseases therapy, Genetic Therapy, Interleukin Receptor Common gamma Subunit genetics, Promoter Regions, Genetic, Proto-Oncogene Proteins c-vav genetics
- Abstract
The efficacy of gene therapy for the treatment of inherited immunodeficiency has been highlighted in recent clinical trials, although in some cases complicated by insertional mutagenesis and silencing of vector genomes through methylation. To minimize these effects, we have evaluated the use of regulatory elements that confer reliability of gene expression, but also lack potent indiscriminate enhancer activity. The Vav1 proximal promoter is particularly attractive in this regard and may be useful in situations where high-level or complex regulation of gene expression is not necessary. X-linked severe combined immunodeficiency (SCID-X1) is a good candidate for such an approach, particularly as there may be additional disease-related intrinsic risks of leukemogenesis, and where safety is therefore a paramount concern. We have tested whether lentiviral vectors expressing the common cytokine receptor gamma chain under the control of the proximal Vav1 gene promoter are effective for correction of signaling defects and the disease phenotype. Despite low-level gene expression, we observed near-complete restoration of cytokine-mediated STAT5 phosphorylation in a model cell line. Furthermore, at low vector copy number, highly effective T- and B-lymphocyte reconstitution was achieved in vivo in a murine model of SCID-X1, in both primary and secondary graft recipients. This vector configuration deserves further evaluation and consideration for future clinical trials.
- Published
- 2011
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14. Lymphomagenesis in SCID-X1 mice following lentivirus-mediated phenotype correction independent of insertional mutagenesis and gammac overexpression.
- Author
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Ginn SL, Liao SH, Dane AP, Hu M, Hyman J, Finnie JW, Zheng M, Cavazzana-Calvo M, Alexander SI, Thrasher AJ, and Alexander IE
- Subjects
- Animals, Cells, Cultured, Enzyme-Linked Immunosorbent Assay, Flow Cytometry, Genetic Therapy adverse effects, Genetic Vectors adverse effects, Genetic Vectors genetics, Interleukin Receptor Common gamma Subunit genetics, Mice, Mice, Inbred C57BL, Mice, SCID, Oligonucleotide Array Sequence Analysis, Polymerase Chain Reaction, Promoter Regions, Genetic genetics, X-Linked Combined Immunodeficiency Diseases genetics, Interleukin Receptor Common gamma Subunit physiology, Lentivirus genetics, Lymphoma etiology, Lymphoma genetics, Mutagenesis, Insertional, X-Linked Combined Immunodeficiency Diseases therapy
- Abstract
The development of leukemia as a consequence of vector-mediated genotoxicity in gene therapy trials for X-linked severe combined immunodeficiency (SCID-X1) has prompted substantial research effort into the design and safety testing of integrating vectors. An important element of vector design is the selection and evaluation of promoter-enhancer elements with sufficient strength to drive reliable immune reconstitution, but minimal propensity for enhancer-mediated insertional mutagenesis. In this study, we set out to explore the effect of promoter-enhancer selection on the efficacy and safety of human immunodeficiency virus-1-derived lentiviral vectors in gammac-deficient mice. We observed incomplete or absent T- and B-cell development in mice transplanted with progenitors expressing gammac from the phosphoglycerate kinase (PGK) and Wiscott-Aldrich syndrome (WAS) promoters, respectively. In contrast, functional T- and B-cell compartments were restored in mice receiving an equivalent vector containing the elongation factor-1-alpha (EF1alpha) promoter; however, 4 of 14 mice reconstituted with this vector subsequently developed lymphoma. Extensive analyses failed to implicate insertional mutagenesis or gammac overexpression as the underlying mechanism. These findings highlight the need for detailed mechanistic analysis of tumor readouts in preclinical animal models assessing vector safety, and suggest the existence of other ill-defined risk factors for oncogenesis, including replicative stress, in gene therapy protocols targeting the hematopoietic compartment.
- Published
- 2010
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15. A novel model of SCID-X1 reconstitution reveals predisposition to retrovirus-induced lymphoma but no evidence of gammaC gene oncogenicity.
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Scobie L, Hector RD, Grant L, Bell M, Nielsen AA, Meikle S, Philbey A, Thrasher AJ, Cameron ER, Blyth K, and Neil JC
- Subjects
- Animals, B-Lymphocytes metabolism, Blotting, Western, CD2 Antigens genetics, Flow Cytometry, Genotype, Humans, Immunophenotyping, In Vitro Techniques, Interleukin Receptor Common gamma Subunit genetics, Lymphoma immunology, Mice, Mice, Transgenic, Polymerase Chain Reaction, Promoter Regions, Genetic genetics, Retroviridae genetics, T-Lymphocytes metabolism, Thymus Gland metabolism, Genetic Therapy adverse effects, Interleukin Receptor Common gamma Subunit physiology, Lymphoma etiology, Lymphoma genetics, Retroviridae physiology, X-Linked Combined Immunodeficiency Diseases genetics, X-Linked Combined Immunodeficiency Diseases therapy
- Abstract
The emergence of leukemia following gene transfer to restore common cytokine receptor gamma chain (gammaC) function in X-linked severe combined immunodeficiency (SCID-X1) has raised important questions with respect to gene therapy safety. To explore the risk factors involved, we tested the oncogenic potential of human gammaC in new strains of transgenic mice expressing the gene under the control of the CD2 promoter and locus control region (LCR). These mice demonstrated mildly perturbed T-cell development, with an increased proportion of thymic CD8 cells, but showed no predisposition to tumor development even on highly tumor prone backgrounds or after gamma-retrovirus infection. The human CD2-gammaC transgene rescued T and B-cell development in gammaC(-/-) mice but with an age-related delay, mimicking postnatal reconstitution in SCID-X1 gene therapy subjects. However, we noted that gammaC(-/-) mice are acutely susceptible to murine leukemia virus (MLV) leukemogenesis, and that this trait was not corrected by the gammaC transgene. We conclude that the SCID-X1 phenotype can be corrected safely by stable ectopic expression of gammaC and that the transgene is not significantly oncogenic when expressed in this context. However, an underlying predisposition conferred by the SCID-X1 background appears to collaborate with insertional mutagenesis to increase the risk of tumor development.
- Published
- 2009
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16. Clinical and immunologic consequences of a somatic reversion in a patient with X-linked severe combined immunodeficiency.
- Author
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Speckmann C, Pannicke U, Wiech E, Schwarz K, Fisch P, Friedrich W, Niehues T, Gilmour K, Buiting K, Schlesier M, Eibel H, Rohr J, Superti-Furga A, Gross-Wieltsch U, and Ehl S
- Subjects
- B-Lymphocytes immunology, B-Lymphocytes pathology, Child, Preschool, Epithelial Cells immunology, Epithelial Cells pathology, Hematopoietic Stem Cell Transplantation, Humans, Interleukin Receptor Common gamma Subunit immunology, Killer Cells, Natural immunology, Killer Cells, Natural pathology, Lymphoid Progenitor Cells immunology, Lymphoid Progenitor Cells pathology, Lymphopenia immunology, Lymphopenia pathology, Lymphopenia therapy, Male, Receptors, Antigen, T-Cell, gamma-delta genetics, Receptors, Antigen, T-Cell, gamma-delta immunology, T-Lymphocytes immunology, T-Lymphocytes pathology, X-Linked Combined Immunodeficiency Diseases immunology, X-Linked Combined Immunodeficiency Diseases pathology, X-Linked Combined Immunodeficiency Diseases therapy, Antibody Formation genetics, Interleukin Receptor Common gamma Subunit genetics, Lymphopenia genetics, Point Mutation, X-Linked Combined Immunodeficiency Diseases genetics
- Abstract
X-linked severe combined immunodeficiency is a life-threatening disorder caused by mutations in the gene encoding the interleukin-2 receptor gamma chain (IL2RG). Hypomorphic mutations and reversion of mutations in subpopulations of cells can result in variant clinical phenotypes, making diagnosis and treatment difficult. We describe a 5-year-old boy with mild susceptibility to infection who was investigated for a mutation in IL2RG due to persistent natural killer (NK)- and T-cell lymphopenia. A functionally relevant novel T466C point mutation was found in B, NK, and epithelial cells, whereas alpha/beta and gamma/delta T cells showed the normal gene sequence, suggesting reversion of the mutation in a common T-cell precursor. This genetic correction in T cells resulted in a diverse T-cell repertoire and significant immunity despite failure to produce specific antibodies linked to an intrinsic defect of mutant B cells. These observations confirm the potential of revertant T-cell precursors to reconstitute immune function, but questions remain on the longevity of revertant cells implicating the need for careful follow up and early consideration of hematopoietic stem cell transplantation (HSCT).
- Published
- 2008
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17. [Analysis of gammac-dependent cytokines-mediated immunoregulation].
- Author
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Asao H
- Subjects
- Animals, Genetic Therapy, Humans, Interleukin Receptor Common gamma Subunit genetics, Interleukins physiology, Mutation, Receptors, Interleukin-2, X-Linked Combined Immunodeficiency Diseases diagnosis, X-Linked Combined Immunodeficiency Diseases immunology, X-Linked Combined Immunodeficiency Diseases therapy, Interleukin Receptor Common gamma Subunit physiology, Lymphocytes immunology
- Abstract
In the study of interleukin-2 (IL-2) -induced signal transduction system, we identified and cloned the third component of IL-2 receptor, IL-2Rgamma chain. Functional high affinity IL-2 receptor consists of three subunits, alpha, beta and gamma chains. Interestingly not only IL-2 but also IL-4, IL-7, IL-9, IL-15 and IL-21 utilize the gamma chain as an essential component of each receptors. Therefore the gamma chain is now called as a common gamma chain (gammac). Moreover the gene of gammac is on the X chromosome, and mutations of gammac gene cause human X-linked severe combined immunodeficiency (X-SCID) characterized by a complete or profound defect of T cells and NK cells, and by the presence of dysfunctional B cells. The dysfunctions in IL-7- and IL-15-induced signal transduction cause the T cell and NK cell defect, respectively and dysfunctions in both IL-4- and IL-21-induced signal transduction cause the B cell dysfunction in X-SCID patients. Gene therapy is a good candidate for X-SCID treatment because only the HLA-matched bone marrow transplantation is an effective therapy. Unfortunately because of an unexpected adverse effect, such gene therapy using retrovirus vector is now aborted. IL-21 is a recently identified cytokine, which shares the gammac. IL-21 regulates the proliferation of T cells, the proliferation and differentiation of B cells, and the activation and expansion of NK cells. We demonstrated that human IL-21 was produced from activated CD4+ central and effector memory T cells but not from naive CD4+ T cells nor CD8+ T cells. Furthermore we found that IL-21 supported cytokine-driven proliferation of CD4+ helper T cells cooperatively with IL-7 and IL-15.
- Published
- 2007
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