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CRISPR-BASED GENE EDITING ENABLES FOXP3GENE REPAIR IN IPEX PATIENT CELLS SCIENCE ADVANCES.

M. Goodwin1*, E. Lee1,2*, U. Lakshmanan1, S. Shipp1, L. Froessl1, F. Barzaghi3,
L. Passerini3, M. Narula1, A. Sheikali1, C. M. Lee4, G. Bao5, C. S. Bauer6, H. K. Miller6, M. Garcia-Lloret7, M. J. Butte7, A. Bertaina1, A. Shah1, M. Pavel-Dinu1, A. Hendel1,8, M. Porteus1,2, M. G. Roncarolo1,2, R. Bacchetta

All publications

Publications

  • Preclinical Safety and Efficacy Validation of CD4(LVFOXP3) Cells as an Innovative Cell-Based Gene Therapy Approach for IPEX Syndrome Sato, Y., Nathan, A., Wright, J., Tate, K., Wani, P., Fazeli, F., Timnak, A., Bhatia, N., Agarwal-Hashmi, R., Bertaina, A., Roncarolo, M., Bacchetta, R. CELL PRESS. 2021: 340
  • Thymic origins of autoimmunity-lessons from inborn errors of immunity. Seminars in immunopathology Bacchetta, R., Weinberg, K. 2021

    Abstract

    During their intrathymic development, nascent T cells are empowered to protect against pathogens and to be operative for a life-long acceptance of self. While autoreactive effector T (Teff) cell progenitors are eliminated by clonal deletion, the intrathymic mechanisms by which thymic regulatory T cell (tTreg) progenitors maintain specificity for self-antigens but escape deletion to exert their regulatory functions are less well understood. Both tTreg and Teff development and selection result from finely coordinated interactions between their clonotypic T cell receptors (TCR) and peptide/MHC complexes expressed by antigen-presenting cells, such as thymic epithelial cells and thymic dendritic cells. tTreg function is dependent on expression of the FOXP3 transcription factor, and induction of FOXP3 gene expression by tTreg occurs during their thymic development, particularly within the thymic medulla. While initial expression of FOXP3 is downstream of TCR activation, constitutive expression is fixed by interactions with various transcription factors that are regulated by other extracellular signals like TCR and cytokines, leading to epigenetic modification of the FOXP3 gene. Most of the understanding of the molecular events underlying tTreg generation is based on studies of murine models, whereas gaining similar insight in the human system has been very challenging. In this review, we will elucidate how inborn errors of immunity illuminate the critical non-redundant roles of certain molecules during tTreg development, shedding light on how their abnormal development and function cause well-defined diseases that manifest with autoimmunity alone or are associated with states of immune deficiency and autoinflammation.

    View details for DOI 10.1007/s00281-020-00835-8

    View details for PubMedID 33532929

  • BHLHE40 Regulates IL-10 and IFN-γ Production in T Cells but Does Not Interfere With Human Type 1 Regulatory T Cell Differentiation Frontiers in Immunology Uyeda, M. J., Freeborn, R. A., Cieniewicz, B., Romano, R., Chen, P. P., Liu, J. M., Thomas, B., Lee, E., Cepika, A., Bacchetta, R., Roncarolo, M. 2021
  • CRISPR-based gene editing enables FOXP3 gene repair in IPEX patient cells SCIENCE ADVANCES Goodwin, M., Lee, E., Lakshmanan, U., Shipp, S., Froessl, L., Barzaghi, F., Passerini, L., Narula, M., Sheikali, A., Lee, C. M., Bao, G., Bauer, C. S., Miller, H. K., Garcia-Lloret, M., Butte, M. J., Bertaina, A., Shah, A., Pavel-Dinu, M., Hendel, A., Porteus, M., Roncarolo, M. G., Bacchetta, R. 2020; 6 (19)
  • Engineered Type-1 Regulatory T Cells as Cellular Therapy for Treatment of Immune Mediated Diseases Liu, J. M., Chen, P., Cieniewicz, B., Cepika, A., Bacchetta, R., Roncarolo, M. AMER ASSOC IMMUNOLOGISTS. 2020
  • A beta T-Cell/CD19 B-Cell Depleted Haploidentical Stem Cell Transplantation: A New Platform for Curing Rare and Monogenic Disorders Bertaina, A., Bacchetta, R., Lewis, D. B., Grimm, P. C., Shah, A. J., Agarwal, R., Concepcion, W., Czechowicz, A., Bhatia, N., Lahiri, P., Weinberg, K. I., Parkman, R., Porteus, M., Roncarolo, M. ELSEVIER SCIENCE INC. 2020: S288
  • Regulatory Type 1 T Cell Infusion in Mismatched Related or Unrelated Hematopoietic Stem Cell Transplantation (HSCT) for Hematologic Malignancies Agarwal, R., Bacchetta, R., Bertaina, A., Chen, P., Saini, G., Shiraz, P., Bhatia, N., Roncarolo, M. ELSEVIER SCIENCE INC. 2020: S272–S273
  • Early Epigenetic Immune Quantification Following Alpha/Beta T-Cell/CD19 B-Cell Depleted Haploidentical Stem Cell Transplant Correlates with CD4+T Cell Recovery at Day+100 Mayers, M., Schulze, J., Barbarito, G., Lakshmanan, U., Parkman, R., Weinberg, K. I., Chu, J., Agarwal, R., Roncarolo, M., Sachsenmaier, C., Bacchetta, R., Bertaina, A. ELSEVIER SCIENCE INC. 2020: S305
  • Human inborn errors of immunity: An expanding universe. Science immunology Notarangelo, L. D., Bacchetta, R. n., Casanova, J. L., Su, H. C. 2020; 5 (49)

    Abstract

    Molecular, cellular, and clinical studies of human inborn errors of immunity have revolutionized our understanding of their pathogenesis, considerably broadened their spectrum of immunological and clinical phenotypes, and enabled successful targeted therapeutic interventions. These studies have also been of great scientific merit, challenging a number of immunological notions initially established in inbred mice while revealing previously unrecognized mechanisms of host defense by leukocytes and other cells and of both innate and adaptive tolerance to self.

    View details for DOI 10.1126/sciimmunol.abb1662

    View details for PubMedID 32651211

  • Hematopoietic Cell Transplantation in Patients With Primary Immune Regulatory Disorders (PIRD): A Primary Immune Deficiency Treatment Consortium (PIDTC) Survey. Frontiers in immunology Chan, A. Y., Leiding, J. W., Liu, X., Logan, B. R., Burroughs, L. M., Allenspach, E. J., Skoda-Smith, S., Uzel, G., Notarangelo, L. D., Slatter, M., Gennery, A. R., Smith, A. R., Pai, S., Jordan, M. B., Marsh, R. A., Cowan, M. J., Dvorak, C. C., Craddock, J. A., Prockop, S. E., Chandrakasan, S., Kapoor, N., Buckley, R. H., Parikh, S., Chellapandian, D., Oshrine, B. R., Bednarski, J. J., Cooper, M. A., Shenoy, S., Davila Saldana, B. J., Forbes, L. R., Martinez, C., Haddad, E., Shyr, D. C., Chen, K., Sullivan, K. E., Heimall, J., Wright, N., Bhatia, M., Cuvelier, G. D., Goldman, F. D., Meyts, I., Miller, H. K., Seidel, M. G., Vander Lugt, M. T., Bacchetta, R., Weinacht, K. G., Andolina, J. R., Caywood, E., Chong, H., de la Morena, M. T., Aquino, V. M., Shereck, E., Walter, J. E., Dorsey, M. J., Seroogy, C. M., Griffith, L. M., Kohn, D. B., Puck, J. M., Pulsipher, M. A., Torgerson, T. R. 2020; 11: 239

    Abstract

    Primary Immune Regulatory Disorders (PIRD) are an expanding group of diseases caused by gene defects in several different immune pathways, such as regulatory T cell function. Patients with PIRD develop clinical manifestations associated with diminished and exaggerated immune responses. Management of these patients is complicated; oftentimes immunosuppressive therapies are insufficient, and patients may require hematopoietic cell transplant (HCT) for treatment. Analysis of HCT data in PIRD patients have previously focused on a single gene defect. This study surveyed transplanted patients with a phenotypic clinical picture consistent with PIRD treated in 33 Primary Immune Deficiency Treatment Consortium centers and European centers. Our data showed that PIRD patients often had immunodeficient and autoimmune features affecting multiple organ systems. Transplantation resulted in resolution of disease manifestations in more than half of the patients with an overall 5-years survival of 67%. This study, the first to encompass disorders across the PIRD spectrum, highlights the need for further research in PIRD management.

    View details for DOI 10.3389/fimmu.2020.00239

    View details for PubMedID 32153572

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