• Identification of unstable regulatory and autoreactive effector T cells that are expanded in patients with FOXP3 mutations. Science translational medicine Borna, Š., Lee, E., Nideffer, J., Ramachandran, A., Wang, B., Baker, J., Mavers, M., Lakshmanan, U., Narula, M., Garrett, A. K., Schulze, J., Olek, S., Marois, L., Gernez, Y., Bhatia, M., Chong, H. J., Walter, J., Kitcharoensakkul, M., Lang, A., Cooper, M. A., Bertaina, A., Roncarolo, M. G., Meffre, E., Bacchetta, R. 2023; 15 (727): eadg6822


    Studies of the monogenic autoimmune disease immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX) have elucidated the essential function of the transcription factor FOXP3 and thymic-derived regulatory T cells (Tregs) in controlling peripheral tolerance. However, the presence and the source of autoreactive T cells in IPEX remain undetermined. Here, we investigated how FOXP3 deficiency affects the T cell receptor (TCR) repertoire and Treg stability in vivo and compared T cell abnormalities in patients with IPEX with those in patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED). To study Tregs independently of their phenotype and to analyze T cell autoreactivity, we combined Treg-specific demethylation region analyses, single-cell multiomic profiling, and bulk TCR sequencing. We found that patients with IPEX, unlike patients with APECED, have expanded autoreactive T cells originating from both autoreactive effector T cells (Teffs) and Tregs. In addition, a fraction of the expanded Tregs from patients with IPEX lost their phenotypic and functional markers, including CD25 and FOXP3. Functional experiments with CRISPR-Cas9-mediated FOXP3 knockout Tregs and Tregs from patients with IPEX indicated that the patients' Tregs gain a TH2-skewed Teff-like function, which is consistent with immune dysregulation observed in these patients. Analyses of FOXP3 mutation-carrier mothers and a patient with IPEX after hematopoietic stem cell transplantation indicated that Tregs expressing nonmutated FOXP3 prevent the accumulation of autoreactive Teffs and unstable Tregs. These findings could be directly used for diagnostic and prognostic purposes and for monitoring the effects of immunomodulatory treatments.

    View details for DOI 10.1126/scitranslmed.adg6822

    View details for PubMedID 38117899

  • A novel FOXP3 knockout-humanized mouse model for pre-clinical safety and efficacy evaluation of Treg-like cell products. Molecular therapy. Methods & clinical development Sato, Y., Nathan, A., Shipp, S., Wright, J. F., Tate, K. M., Wani, P., Roncarolo, M. G., Bacchetta, R. 2023; 31: 101150


    Forkhead box P3 (FOXP3) is an essential transcription factor for regulatory T cell (Treg) function. Defects in Tregs mediate many immune diseases including the monogenic autoimmune disease immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX), which is caused by FOXP3 mutations. Treg cell products are a promising modality to induce allograft tolerance or reduce the use of immunosuppressive drugs to prevent rejection, as well as in the treatment of acquired autoimmune diseases. We have recently opened a phase I clinical trial for IPEX patients using autologous engineered Treg-like cells, CD4LVFOXP3. To facilitate the pre-clinical studies, a novel humanized-mouse (hu-mouse) model was developed whereby immune-deficient mice were transplanted with human hematopoietic stem progenitor cells (HSPCs) in which the FOXP3 gene was knocked out (FOXP3KO) using CRISPR-Cas9. Mice transplanted with FOXP3KO HSPCs had impaired survival, developed lymphoproliferation 10-12 weeks post-transplant and T cell infiltration of the gut, resembling human IPEX. Strikingly, injection of CD4LVFOXP3 into the FOXP3KO hu-mice restored in vivo regulatory functions, including control of lymphoproliferation and inhibition of T cell infiltration in the colon. This hu-mouse disease model can be reproducibly established and constitutes an ideal model to assess pre-clinical efficacy of human Treg cell investigational products.

    View details for DOI 10.1016/j.omtm.2023.101150

    View details for PubMedID 38027059

    View details for PubMedCentralID PMC10679769

  • IPEX Syndrome from diagnosis to cure, learning along the way. The Journal of allergy and clinical immunology Bacchetta, R., Roncarolo, M. G. 2023


    In the past two decades, a significant number of studies have been published describing the molecular and clinical aspects of Immune dysregulation Polyendocrinopathy Enteropathy X-linked Syndrome (IPEX). These studies have refined our knowledge of this rare yet prototypic genetic autoimmune disease, advancing the diagnosis, broadening the clinical spectrum, and improving our understanding of the underlying immunological mechanisms. Despite these advances, Forkhead box P3 (FOXP3) mutations have devastating consequences, and treating patients with IPEX remains a challenge even with safer strategies for hematopoietic stem cell transplantation, and gene therapy becoming a promising reality. The aim of this review is to highlight novel features of the disease to further advance awareness and improve the diagnosis and treatment of patients with IPEX Syndrome.

    View details for DOI 10.1016/j.jaci.2023.11.021

    View details for PubMedID 38040040

  • Radiation and Busulfan-Free Hematopoietic Stem Cell Transplantation Using Briquilimab (JSP191) Anti-CD117 Antibody-Conditioning, Transient Immunosuppression and TCR α β + T-Cell/CD19+B-Cell Depleted Haploidentical Grafts in Patients with Fanconi Anemia Agarwal, R., Bertaina, A., Soco, C., Saini, G., Kunte, N., Hiroshima, L., Chan, Y., Willner, H., Krampf, M. L., Nofal, R., Barbarito, G., Sen, S., Felber, M., Van Hentenryck, M., Walck, E., Scheck, A., Thongthip, S., Logan, A. C., Dougall, K., Bouge, A., Boelens, J., Long-Boyle, J. R., Weissman, I. L., Shizuru, J., Pang, W. W., Weinberg, K. I., Parkman, R., Roncarolo, M., Porteus, M., Czechowicz, A. AMER SOC HEMATOLOGY. 2023
  • LENTIVIRAL-MEDIATED GENE THERAPY FOR SEVERE PYRUVATE KINASE DEFICIENCY: RESULTS FROM AN ONGOING GLOBAL PHASE 1 STUDY Lopez Lorenzo, J., Shah, A., Sevilla, J., Navarro, S., Llanos, L., de Camino Gaisse, B., Sanchez, S., Zubicaray, J., Glader, B., Chien, M., Quintana Bustamante, O., Zeini, M., Choi, G., Nicoletti, E., Rao, G., Roncarolo, M., Bueren, J., Schwartz, J., Carlos Segovia, J. SPRINGERNATURE. 2023: 275-276
  • LENTIVIRAL-MEDIATED GENE THERAPY FOR PATIENTS WITH FANCONI ANEMIA [GROUP A]: UPDATED RESULTS FROM GLOBAL RP-L102 CLINICAL TRIALS Sevilla, J., Booth, C., Czechowicz, A., Agarwal, R., Zubicaray, J., Rio, P., Chetty, K., O'Toole, G., Xu-Bayford, J., Ancliff, P., Sebastian, E., Choi, G., Zeini, M., Nicoletti, E., Eide, C., Wagner, J., Rao, G., Thrasher, A., Schwartz, J., Roncarolo, M., Bueren, J. SPRINGERNATURE. 2023: 276-277
  • T-ALLO10 INFUSION AFTER A.DEPLETED-HSCT IN CHILDREN AND YOUNG ADULTS WITH HEMATOLOGIC MALIGNANCIES: IMPROVED IMMUNE RECONSTITUTION IN THE ABSENCE OF SEVERE GVHD Bertaina, A., Bacchetta, R., Shyr, D., Saini, G., Lee, J., Kristovich, K., Agarwal-Hashmi, R., Klein, O., Melsop, K., Tate, K., Barbarito, G., Oppizzi, L., Chen, P., Cepika, A., Roncarolo, M. SPRINGERNATURE. 2023: 232-234
  • LENTIVIRAL-MEDIATED GENE THERAPY FOR FANCONI ANEMIA [GROUP A]: RESULTS FROM RP-L102 CLINICAL TRIALS Czechowicz, A., Sevilla, J., Booth, C., Agarwal, R., Zubicaray, J., Rio, P., Navarro, S., Chetty, K., O'Toole, G., Xu-Bayford, J., Ancliff, P., Sebastian, E., Choi, G., Zeini, M., Nicoletti, E., Wagner, J., Eide, C., Rao, G., Thrasher, A., Schwartz, J., Roncarolo, M., Bueren, J. WILEY. 2023: S136-S137
  • LENTIVIRAL-MEDIATED GENE THERAPY FOR SEVERE PYRUVATE KINASE DEFICIENCY: GLOBAL PHASE 1 STUDY RESULTS Shah, A., Lorenzo, J., Sevilla, J., Navarro, S., Llanos, L., Gaisse, B., Sanchez, S., Zubicaray, J., Glader, B., Chien, M., Bustamante, O. Q., Zeini, M., Choi, G., Nicoletti, E., Rao, G., Roncarolo, M., Bueren, J., Schwartz, J., Segovia, J. WILEY. 2023: S133-S134
  • Discovery of Key Transcriptional Regulators of Alloantigen-Inducible Tregs Used for Cell Therapy Cepika, A., Amaya, L., Waichler, C., Narula, M., Thomas, B. C., Chen, P. P., Mantilla, M. M., Pavel-Dinu, M., Freeborn, R., Porteus, M. H., Bacchetta, R., Mueller, F., Greenleaf, W. J., Chang, H. Y., Roncarolo, M. CELL PRESS. 2023: 370-371

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