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Recombination-activating gene 1 (Rag1)-deficient mice with severe combined immunodeficiency treated with lentiviral gene therapy demonstrate autoimmune Omenn-like syndrome.
J Allergy Clin Immunol. 2014 Apr; 133(4):1116-23.JA

Abstract

BACKGROUND

Recombination-activating gene 1 (RAG1) deficiency results in severe combined immunodeficiency (SCID) caused by a complete lack of T and B lymphocytes. If untreated, patients succumb to recurrent infections.

OBJECTIVES

We sought to develop lentiviral gene therapy for RAG1-induced SCID and to test its safety.

METHODS

Constructs containing the viral spleen-focus-forming virus (SF), ubiquitous promoters, or cell type-restricted promoters driving sequence-optimized RAG1 were compared for efficacy and safety in sublethally preconditioned Rag1(-/-) mice undergoing transplantation with transduced bone marrow progenitors.

RESULTS

Peripheral blood CD3(+) T-cell reconstitution was achieved with SF, ubiquitous promoters, and cell type-restricted promoters but 3- to 18-fold lower than that seen in wild-type mice, and with a compromised CD4(+)/CD8(+) ratio. Mitogen-mediated T-cell responses and T cell-dependent and T cell-independent B-cell responses were not restored, and T-cell receptor patterns were skewed. Reconstitution of mature peripheral blood B cells was approximately 20-fold less for the SF vector than in wild-type mice and often not detectable with the other promoters, and plasma immunoglobulin levels were abnormal. Two months after transplantation, gene therapy-treated mice had rashes with cellular tissue infiltrates, activated peripheral blood CD44(+)CD69(+) T cells, high plasma IgE levels, antibodies against double-stranded DNA, and increased B cell-activating factor levels. Only rather high SF vector copy numbers could boost T- and B-cell reconstitution, but mRNA expression levels during T- and B-cell progenitor stages consistently remained less than wild-type levels.

CONCLUSIONS

These results underline that further development is required for improved expression to successfully treat patients with RAG1-induced SCID while maintaining low vector copy numbers and minimizing potential risks, including autoimmune reactions resembling Omenn syndrome.

Authors+Show Affiliations

Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands.Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands.Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands.INSERM U768, Université René Descartes, and Hôpital Necker-Enfants Malades, Paris, France; Department of Pediatric Oncology, Hematology and Clinical Immunology, Center for Child and Adolescent Health, Heinrich Heine University, Düsseldorf, Germany.INSERM U768, Université René Descartes, and Hôpital Necker-Enfants Malades, Paris, France.Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands.Immunology Institute, Department of Medicine, Mount Sinai School of Medicine, New York, NY.Immunology Institute, Department of Medicine, Mount Sinai School of Medicine, New York, NY.INSERM U781 Laboratoire de transfert de gènes, Hôpital Necker-Enfants Malades, Paris, France.INSERM U781 Laboratoire de transfert de gènes, Hôpital Necker-Enfants Malades, Paris, France.CNR-IRGB, Milan Unit, Milan, Italy; Humanitas Clinical and Research Center, Milan, Italy.Molecular Immunology Unit, Centre for Immunodeficiency, Institute of Child Health, University College London, London, United Kingdom.Molecular Immunology Unit, Centre for Immunodeficiency, Institute of Child Health, University College London, London, United Kingdom.Department of Pathology, University of Brescia, Brescia, Italy.Department of Pathology, University of Brescia, Brescia, Italy.INSERM U768, Université René Descartes, and Hôpital Necker-Enfants Malades, Paris, France; Department of Biotherapy, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (AP-HP), Université René Descartes, and INSERM, Centre d'Investigation Clinique intégré en Biothérapies, Groupe Hospitalier Universitaire Ouest, AP-HP, Paris, France.Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands.CNR-IRGB, Milan Unit, Milan, Italy; Telethon Institute for Gene Therapy-H San Raffaele, Milan, Italy.Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands. Electronic address: g.wagemaker@genetherapy.nl.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24332219

Citation

van Til, Niek P., et al. "Recombination-activating Gene 1 (Rag1)-deficient Mice With Severe Combined Immunodeficiency Treated With Lentiviral Gene Therapy Demonstrate Autoimmune Omenn-like Syndrome." The Journal of Allergy and Clinical Immunology, vol. 133, no. 4, 2014, pp. 1116-23.
van Til NP, Sarwari R, Visser TP, et al. Recombination-activating gene 1 (Rag1)-deficient mice with severe combined immunodeficiency treated with lentiviral gene therapy demonstrate autoimmune Omenn-like syndrome. J Allergy Clin Immunol. 2014;133(4):1116-23.
van Til, N. P., Sarwari, R., Visser, T. P., Hauer, J., Lagresle-Peyrou, C., van der Velden, G., Malshetty, V., Cortes, P., Jollet, A., Danos, O., Cassani, B., Zhang, F., Thrasher, A. J., Fontana, E., Poliani, P. L., Cavazzana, M., Verstegen, M. M., Villa, A., & Wagemaker, G. (2014). Recombination-activating gene 1 (Rag1)-deficient mice with severe combined immunodeficiency treated with lentiviral gene therapy demonstrate autoimmune Omenn-like syndrome. The Journal of Allergy and Clinical Immunology, 133(4), 1116-23. https://doi.org/10.1016/j.jaci.2013.10.009
van Til NP, et al. Recombination-activating Gene 1 (Rag1)-deficient Mice With Severe Combined Immunodeficiency Treated With Lentiviral Gene Therapy Demonstrate Autoimmune Omenn-like Syndrome. J Allergy Clin Immunol. 2014;133(4):1116-23. PubMed PMID: 24332219.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Recombination-activating gene 1 (Rag1)-deficient mice with severe combined immunodeficiency treated with lentiviral gene therapy demonstrate autoimmune Omenn-like syndrome. AU - van Til,Niek P, AU - Sarwari,Roya, AU - Visser,Trudi P, AU - Hauer,Julia, AU - Lagresle-Peyrou,Chantal, AU - van der Velden,Guus, AU - Malshetty,Vidyasagar, AU - Cortes,Patricia, AU - Jollet,Arnaud, AU - Danos,Olivier, AU - Cassani,Barbara, AU - Zhang,Fang, AU - Thrasher,Adrian J, AU - Fontana,Elena, AU - Poliani,Pietro L, AU - Cavazzana,Marina, AU - Verstegen,Monique M A, AU - Villa,Anna, AU - Wagemaker,Gerard, Y1 - 2013/12/09/ PY - 2013/01/03/received PY - 2013/10/04/revised PY - 2013/10/09/accepted PY - 2013/12/17/entrez PY - 2013/12/18/pubmed PY - 2014/6/17/medline KW - Severe combined immunodeficiency KW - autoimmune reactions KW - lentiviral gene therapy SP - 1116 EP - 23 JF - The Journal of allergy and clinical immunology JO - J. Allergy Clin. Immunol. VL - 133 IS - 4 N2 - BACKGROUND: Recombination-activating gene 1 (RAG1) deficiency results in severe combined immunodeficiency (SCID) caused by a complete lack of T and B lymphocytes. If untreated, patients succumb to recurrent infections. OBJECTIVES: We sought to develop lentiviral gene therapy for RAG1-induced SCID and to test its safety. METHODS: Constructs containing the viral spleen-focus-forming virus (SF), ubiquitous promoters, or cell type-restricted promoters driving sequence-optimized RAG1 were compared for efficacy and safety in sublethally preconditioned Rag1(-/-) mice undergoing transplantation with transduced bone marrow progenitors. RESULTS: Peripheral blood CD3(+) T-cell reconstitution was achieved with SF, ubiquitous promoters, and cell type-restricted promoters but 3- to 18-fold lower than that seen in wild-type mice, and with a compromised CD4(+)/CD8(+) ratio. Mitogen-mediated T-cell responses and T cell-dependent and T cell-independent B-cell responses were not restored, and T-cell receptor patterns were skewed. Reconstitution of mature peripheral blood B cells was approximately 20-fold less for the SF vector than in wild-type mice and often not detectable with the other promoters, and plasma immunoglobulin levels were abnormal. Two months after transplantation, gene therapy-treated mice had rashes with cellular tissue infiltrates, activated peripheral blood CD44(+)CD69(+) T cells, high plasma IgE levels, antibodies against double-stranded DNA, and increased B cell-activating factor levels. Only rather high SF vector copy numbers could boost T- and B-cell reconstitution, but mRNA expression levels during T- and B-cell progenitor stages consistently remained less than wild-type levels. CONCLUSIONS: These results underline that further development is required for improved expression to successfully treat patients with RAG1-induced SCID while maintaining low vector copy numbers and minimizing potential risks, including autoimmune reactions resembling Omenn syndrome. SN - 1097-6825 UR - https://www.unboundmedicine.com/medline/citation/24332219/Recombination_activating_gene_1__Rag1__deficient_mice_with_severe_combined_immunodeficiency_treated_with_lentiviral_gene_therapy_demonstrate_autoimmune_Omenn_like_syndrome_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0091-6749(13)01560-1 DB - PRIME DP - Unbound Medicine ER -