Efficacy of lentiviral mediated gene therapy in an Omenn syndrome Rag2 mouse model is not hindered by inflammation and immune dysregulation

Publication date: Available online 11 December 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): 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
BackgroundOmenn syndrome (OS) is a rare severe combined immunodeficiency associated with autoimmunity, caused by defects of the lymphoid-specific V(D)J recombination. Most patients carry hypomorphic mutations in recombination activating genes (RAG) 1 or 2. Hematopoietic stem cell (HSC) transplantation is the standard treatment, however gene therapy (GT) may represent a valid alternative, especially for patients lacking a matched donor.ObjectiveTo determine the efficacy of lentiviral vector (LV) mediated GT in the murine model of OS (Rag2^R229Q/R229Q) in correcting immunodeficiency and autoimmunity.MethodsOS Lin^- cells were transduced with a LV encoding the human RAG2 gene and injected into irradiated OS recipients. Control mice were transplanted with wild-type or OS untransduced Lin- cells. Immunophenotype, T-dependent and independent antigen challenges, immune spectratyping, autoantibodies detection and detailed tissue immunohistochemical analyses were performed.ResultsLV-mediated GT allowed immunological reconstitution, although suboptimal as compared to wild type bone marrow transplanted OS mice, in peripheral blood and hematopoietic organs, such as bone marrow, 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 properly responded 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 bone marrow and 2 in the thymus.ConclusionsOur data show that LV-mediated GT for Omenn Syndrome significantly ameliorates the immunodeficiency even in an inflammatory environment.



http://ift.tt/2kpymg9