Efficacy of lentivirus-mediated gene therapy in an Omenn syndrome recombination-activating gene 2 mouse model is not hindered by inflammation and immune dysregulation

Valentina Capo, Maria Carmina Castiello, Elena Fontana, Sara Penna, Marita Bosticardo, Elena Draghici, Luigi P Poliani, Lucia Sergi Sergi, Rosita Rigoni, Barbara Cassani, Monica Zanussi, Paola Carrera, Paolo Uva, Kerry Dobbs, Nicolò Sacchetti, Luigi D Notarangelo, Niek P van Til, Gerard Wagemaker, Anna Villa

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Abstract

BACKGROUND: Omenn syndrome (OS) is a rare severe combined immunodeficiency associated with autoimmunity and caused by defects in lymphoid-specific V(D)J recombination. Most patients carry hypomorphic mutations in recombination-activating gene (RAG) 1 or 2. Hematopoietic stem cell transplantation is the standard treatment; however, gene therapy (GT) might represent a valid alternative, especially for patients lacking a matched donor.

OBJECTIVE: We sought to determine the efficacy of lentiviral vector (LV)-mediated GT in the murine model of OS (Rag2R229Q/R229Q) in correcting immunodeficiency and autoimmunity.

METHODS: Lineage-negative cells from mice with OS were transduced with an LV encoding the human RAG2 gene and injected into irradiated recipients with OS. Control mice underwent transplantation with wild-type or OS-untransduced lineage-negative cells. Immunophenotyping, T-dependent and T-independent antigen challenge, immune spectratyping, autoantibody detection, and detailed tissue immunohistochemical analyses were performed.

RESULTS: LV-mediated GT allowed immunologic reconstitution, although it was suboptimal compared with that seen in wild-type bone marrow (BM)-transplanted OS mice in peripheral blood and hematopoietic organs, such as the BM, thymus, and spleen. We observed in vivo variability in the efficacy of GT correlating with the levels of transduction achieved. Immunoglobulin levels and T-cell repertoire normalized, and gene-corrected mice responded properly to challenges in vivo. Autoimmune manifestations, such as skin infiltration and autoantibodies, dramatically improved in GT mice with a vector copy number/genome higher than 1 in the BM and 2 in the thymus.

CONCLUSIONS: Our data show that LV-mediated GT for patients with OS significantly ameliorates the immunodeficiency, even in an inflammatory environment.

Original languageEnglish
JournalJournal of Allergy and Clinical Immunology
DOIs
Publication statusE-pub ahead of print - Dec 11 2017

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Capo, V., Castiello, M. C., Fontana, E., Penna, S., Bosticardo, M., Draghici, E., Poliani, L. P., Sergi Sergi, L., Rigoni, R., Cassani, B., Zanussi, M., Carrera, P., Uva, P., Dobbs, K., Sacchetti, N., Notarangelo, L. D., van Til, N. P., Wagemaker, G., & Villa, A. (2017). Efficacy of lentivirus-mediated gene therapy in an Omenn syndrome recombination-activating gene 2 mouse model is not hindered by inflammation and immune dysregulation. Journal of Allergy and Clinical Immunology. https://doi.org/10.1016/j.jaci.2017.11.015