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

Author

Capo, V, Castiello, M, Fontana, E, Penna, S, Bosticardo, M, Draghici, E, Poliani, L, Sergi Sergi, L, Rigoni, R, Cassani, B, Zanussi, M, Carrera, P, Uva, P, Dobbs, K, Sacchetti, N, Notarangelo, L, van Til, N, Wagemaker, G, Villa, A, Castiello, MC, Poliani, LP, Notarangelo, LD, van Til N. P., Capo, V, Castiello, M, Fontana, E, Penna, S, Bosticardo, M, Draghici, E, Poliani, L, Sergi Sergi, L, Rigoni, R, Cassani, B, Zanussi, M, Carrera, P, Uva, P, Dobbs, K, Sacchetti, N, Notarangelo, L, van Til, N, Wagemaker, G, Villa, A, Castiello, MC, Poliani, LP, Notarangelo, LD, and van Til N. P.

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 (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.

Published
2018

4. Efficacy Of Lentivirus-Mediated Gene Therapy In An Omenn Syndrome Recombination-Activating Gene 2 Mouse Model Is Not Hindered By Inflammation And Immune Dysregulation

Author

Anna Villa, Paola Carrera, Marita Bosticardo, Elena Fontana, Maria Carmina Castiello, Sara Penna, Monica Zanussi, Lucia Sergi Sergi, Elena Draghici, Luigi Poliani, Nicolò Sacchetti, Gerard Wagemaker, Valentina Capo, Barbara Cassani, Luigi D. Notarangelo, Niek P. van Til, Kerry Dobbs, Rosita Rigoni, Paolo Uva, İç Hastalıkları, Hematology, Capo, V, Castiello, M, Fontana, E, Penna, S, Bosticardo, M, Draghici, E, Poliani, L, Sergi Sergi, L, Rigoni, R, Cassani, B, Zanussi, M, Carrera, P, Uva, P, Dobbs, K, Sacchetti, N, Notarangelo, L, van Til, N, Wagemaker, G, and Villa, A

Subjects
Male, 0301 basic medicine, Rag gene, Allergy, T-Lymphocytes, Genetic enhancement, Immunology, Autoimmunity, Mice, Transgenic, Article, Gene therapy, Lentiviral vector, Omenn syndrome, Rag genes, Immunology and Allergy, 03 medical and health sciences, RAG2, medicine, Animals, Lymphocyte Count, Immunodeficiency, Inflammation, B-Lymphocytes, Severe combined immunodeficiency, business.industry, Lentivirus, Genetic Therapy, medicine.disease, Autoimmune regulator, 3. Good health, DNA-Binding Proteins, Mice, Inbred C57BL, Transplantation, Disease Models, Animal, 030104 developmental biology, Primary immunodeficiency, Female, Severe Combined Immunodeficiency, business
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 (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.

Published
2018

5. Gender differences in expression of androgen receptor in tibial growth plate and metaphyseal bone of the rat.

Author

van der Eerden BC, van Til NP, Brinkmann AO, Lowik CW, Wit JM, and Karperien M

Subjects
Animals, Epiphyses chemistry, Epiphyses metabolism, Epiphyses physiology, Female, Gene Expression physiology, Growth Plate chemistry, Growth Plate physiology, Male, RNA, Messenger biosynthesis, Rats, Rats, Wistar, Receptors, Androgen analysis, Sexual Maturation physiology, Tibia chemistry, Tibia physiology, Growth Plate metabolism, Receptors, Androgen biosynthesis, Sex Characteristics, Tibia metabolism
Abstract

In this study, we investigate the expression of the androgen receptor (AR) in the tibial growth plate and metaphyseal bone of male and female rats at the mRNA and protein level. Using in situ hybridization and immunohistochemistry, AR mRNA and protein were demonstrated in proliferating and early hypertrophic chondrocytes in the growth plate of 1-, 4-, and 7-week-old male and female rats. Immunostaining for AR was observed both in the nucleus and the cytoplasm. After sexual maturation at 12 and 16 weeks of age, AR expression decreased in both genders and was confined to a small rim of prehypertrophic chondrocytes. In female rats of 40 weeks of age, this expression pattern was still visible. In most age groups there was a tendency toward an increased AR mRNA expression in male vs. female rats except in the 7-week-old animals. At the protein level, sexually maturing 7-week-old male rats demonstrated a higher staining intensity compared to their female counterparts. At this stage, AR staining in the males was mainly confined to the nucleus, whereas in females staining was predominantly found in the cytoplasm. In the tibial metaphysis, AR mRNA was detected in lining cells, osteoblasts, osteocytes, and osteoclasts at all stages of development. At the protein level, a similar expression pattern was observed, except for an absence of immunostaining in the lining cells. The staining was both nuclear and cytoplasmic. In most age groups, mRNA and protein signals were higher in males compared with females. We have demonstrated the presence of AR mRNA and protein in the tibial growth plate and the underlying metaphyseal bone during development of the rat. In male rats, the presence of higher messenger and protein staining intensities, as well as preferential nuclear staining during sexual maturation, suggests that direct actions of androgens in chondrocytes and in bone forming cells may be involved in establishing the gender differences in the skeleton.

Published
2002
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