Recombination-activating gene 1 (Rag1)-deficient mice with severe combined immunodeficiency treated with lentiviral gene therapy demonstrate autoimmune Omenn-like syndrome

Niek P. Van Til, Roya Sarwari, Trudi P. Visser, Julia Hauer, Chantal Lagresle-Peyrou, Guus Van Der Velden, Vidyasagar Malshetty, Patricia Cortes, Arnaud Jollet, Olivier Danos, Barbara Cassani, Fang Zhang, Adrian J. Thrasher, Elena Fontana, Pietro L. Poliani, Marina Cavazzana, Monique M A Verstegen, Anna Villa, Gerard Wagemaker

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)1116-1123
Number of pages8
JournalJournal of Allergy and Clinical Immunology
Volume133
Issue number4
DOIs
Publication statusPublished - 2014

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RAG-1 Genes
Severe Combined Immunodeficiency
Spleen Focus-Forming Viruses
Genetic Therapy
T-Lymphocytes
B-Lymphocytes
Transplantation
B-Cell Activating Factor
Safety
CD4-CD8 Ratio
B-Lymphoid Precursor Cells
T-Cell Antigen Receptor
Exanthema
Mitogens
Immunoglobulin E
Immunoglobulins
Blood Cells
Bone Marrow
Messenger RNA
Antibodies

Keywords

  • autoimmune reactions
  • lentiviral gene therapy
  • Severe combined immunodeficiency

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Recombination-activating gene 1 (Rag1)-deficient mice with severe combined immunodeficiency treated with lentiviral gene therapy demonstrate autoimmune Omenn-like syndrome. / Van Til, Niek P.; Sarwari, Roya; Visser, Trudi P.; Hauer, Julia; Lagresle-Peyrou, Chantal; Van Der Velden, Guus; Malshetty, Vidyasagar; Cortes, Patricia; Jollet, Arnaud; Danos, Olivier; Cassani, Barbara; Zhang, Fang; Thrasher, Adrian J.; Fontana, Elena; Poliani, Pietro L.; Cavazzana, Marina; Verstegen, Monique M A; Villa, Anna; Wagemaker, Gerard.

In: Journal of Allergy and Clinical Immunology, Vol. 133, No. 4, 2014, p. 1116-1123.

Research output: Contribution to journalArticle

Van Til, NP, Sarwari, R, Visser, TP, Hauer, J, Lagresle-Peyrou, C, Van Der Velden, G, Malshetty, V, Cortes, P, Jollet, A, Danos, O, Cassani, B, Zhang, F, Thrasher, AJ, Fontana, E, Poliani, PL, Cavazzana, M, Verstegen, MMA, 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', Journal of Allergy and Clinical Immunology, vol. 133, no. 4, pp. 1116-1123. https://doi.org/10.1016/j.jaci.2013.10.009
Van Til, Niek P. ; Sarwari, Roya ; Visser, Trudi P. ; Hauer, Julia ; Lagresle-Peyrou, Chantal ; Van Der Velden, Guus ; Malshetty, Vidyasagar ; Cortes, Patricia ; Jollet, Arnaud ; Danos, Olivier ; Cassani, Barbara ; Zhang, Fang ; Thrasher, Adrian J. ; Fontana, Elena ; Poliani, Pietro L. ; Cavazzana, Marina ; Verstegen, Monique M A ; Villa, Anna ; Wagemaker, Gerard. / Recombination-activating gene 1 (Rag1)-deficient mice with severe combined immunodeficiency treated with lentiviral gene therapy demonstrate autoimmune Omenn-like syndrome. In: Journal of Allergy and Clinical Immunology. 2014 ; Vol. 133, No. 4. pp. 1116-1123.
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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.",
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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

PY - 2014

Y1 - 2014

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.

AB - 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.

KW - autoimmune reactions

KW - lentiviral gene therapy

KW - Severe combined immunodeficiency

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