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 journalArticlepeer-review


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
Issue number4
Publication statusPublished - 2014


  • autoimmune reactions
  • lentiviral gene therapy
  • Severe combined immunodeficiency

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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