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

卷:142

Article

Capo, Valentina¹  Castiello, Maria Carmina¹  Fontana, Elena^3,5  Penna, Sara¹  Bosticardo, Marita¹  Draghici, Elena¹  Poliani, Luigi P.⁴  Sergi, Lucia Sergi¹  Rigoni, Rosita^3,5  Cassani, Barbara^3,5  Zanussi, Monica²  Carrera, Paola²  Uva, Paolo⁶  Dobbs, Kerry⁷  Sacchetti, Nicole^1,8  Notarangelo, Luigi D.⁷  van Til, Niek P.^9,10  Wagemaker, Gerard^9,11,12  Villa, Anna^1,5 

[1] Ist Sci San Raffaele, Div Regenerat Med Stem Cells & Gene Therapy, San Raffaele Telethon Inst Gene Therapy SR TIGET, Via Olgettina 60, I-20132 Milan, Italy

[2] Ist Sci San Raffaele, Genom Diag Human Pathol, Milan, Italy

[3] Humanitas Clin & Res Ctr, Milan, Italy

[4] Univ Hosp Spedali Civili, Inst Mol Med A Nocivelli, Brescia, Italy

[5] CNR, Milan Unit, Ist Ric Genet & Biomed, Milan, Italy

[6] CRS4, Sci & Technol Pk Polaris, Pula, Croatia

[7] NIAID, Lab Host Def, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA

[8] Univ Vita Salute San Raffaele, Milan, Italy

[9] Erasmus Univ, Dept Hematol, Med Ctr, Rotterdam, Netherlands

[10] Univ Med Ctr Utrecht, Lab Translat Immunol, Utrecht, Netherlands

[11] Hacettepe Univ, Stem Cell Res & Dev Ctr, Ankara, Turkey

[12] Raisa Gorbacheva Mem Res Inst Pediat Oncol & Hema, St Petersburg, Russia

关键词: Gene therapy;    Omenn syndrome;    auto immunity;    lentiviral vector;    Rag genes;   

DOI  :  10.1016/j.jaci.2017.11.015

来源: Elsevier

【 摘 要 】

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 (Rag2(R229Q/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.

【 授权许可】

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