Publications

Publications

  • 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
  • Global Phase 1 Study Results of Lentiviral Mediated Gene Therapy for Severe Pyruvate Kinase Deficiency Shah, A. J., Lopez Lorenzo, J., 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. A., Schwartz, J., Carlos Segovia, J. CELL PRESS. 2023: 118-119
  • Lentiviral-Mediated Gene Therapy for Fanconi Anemia [Group A]: Results from Global RP-L102 Clinical Trials Czechowicz, A., Sevilla, J., Booth, C., Navarro, S., 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. E., Rao, G., Thrasher, A. J., Schwartz, J., Roncarolo, M., Bueren, J. A. CELL PRESS. 2023: 118
  • SATB1 chromatin loops regulate Megakaryocyte/Erythroid Progenitor Expansion by facilitating HSP70 and GATA1 induction. Stem cells (Dayton, Ohio) Wilkes, M. C., Chae, H. D., Scanlon, V., Cepika, A. M., Wentworth, E. P., Saxena, M., Eskin, A., Chen, Z., Glader, B., Roncarolo, M. G., Nelson, S. F., Sakamoto, K. M. 2023

    Abstract

    Diamond Blackfan Anemia (DBA) is an inherited bone marrow failure syndrome associated with severe anemia, congenital malformations and increased risk of developing cancer. The chromatin-binding SATB1 is downregulated in Megakaryocyte/Erythroid Progenitors (MEPs) in patients and cell models of DBA, leading to a reduction in MEP expansion. Here we demonstrate that SATB1 expression is required for the upregulation of the critical erythroid factors HSP70 and GATA1 that accompanies MEP differentiation. SATB1 binding to specific sites surrounding the HSP70 genes, promotes chromatin loops that are required for induction of HSP70, which in turn promotes GATA1 induction. This demonstrates that SATB1, although gradually downregulated during myelopoiesis, maintains a biological function in early myeloid progenitors.

    View details for DOI 10.1093/stmcls/sxad025

    View details for PubMedID 36987811

  • Hematopoietic and Immunological Assessment in Fanconi Anemia after Ex Vivo Lentiviral FANCA Gene Therapy with RP-L102 Nofal, R., Chan, Y., Sen, S., Figueroa, U., Willner, H., Felber, M., Krampf, M., Thongthip, S., Choi, G., Nicoletti, E., Schwartz, J. D., Weinberg, K., Rodriguez, A., Agarwal, R., Roncarolo, M., Czechowicz, A. AMER SOC HEMATOLOGY. 2022: 7772-7773
  • Lentiviral-mediated Gene Therapy for Patients with Fanconi Anemia [Group A]: Updated Results from Global 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. E., Rao, G. R., Thrasher, A. J., Schwartz, J. D., Roncarolo, M., Bueren, J. A. AMER SOC HEMATOLOGY. 2022: 10646-10647
  • Epigenetic and Immunological Indicators of IPEX Disease in subjects with FOXP3 gene mutation. The Journal of allergy and clinical immunology Narula, M., Lakshmanan, U., Borna, S., Schulze, J. J., Holmes, T. H., Harre, N., Kirkey, M., Ramachandran, A., Tagi, V. M., Barzaghi, F., Grunebaum, E., Upton, J. E., Hong-Diep Kim, V., Wysocki, C., Dimitriades, V. R., Weinberg, K., Weinacht, K. G., Gernez, Y., Sathi, B. K., Schelotto, M., Johnson, M., Olek, S., Sachsenmaier, C., Roncarolo, M. G., Bacchetta, R. 2022

    Abstract

    Forkhead-Box-Protein-3 (FOXP3) is the master transcription factor in CD4+CD25hiCD127lo regulatory T (Treg) cells. Mutations in FOXP3 result in IPEX (Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-linked) syndrome. Clinical presentation of IPEX syndrome is broader than initially described, challenging the understanding of the disease, its evolution and treatment choice.To study the type and extent of immunological abnormalities which remain ill-defined in IPEX, across genetic and clinical heterogeneity.We performed Treg-specific epigenetic quantification and immunological characterization of severe "typical" (n=6) and "atypical" or asymptomatic (n=9) IPEX patients.Increased number of cells with Treg-Specific Demethylated Region (TSDR) demethylation in FOXP3 is a consistent feature in IPEX patients, with i) highest values in those with typical IPEX, ii) increased values in subjects with pathogenic FOXP3 but still no symptoms, and iii) gradual increase over the course of disease progression. Large scale profiling using Luminex identified plasma inflammatory signature of macrophage activation and Th2 polarization, with cytokines previously not associated with IPEX pathology, including CCL22, CCL17, CCL15, and IL-13, and the inflammatory markers TNF╬▒, IL-1A, IL-8, sFasL, and CXCL9. Similarly, both Treg and Teff compartments, studied by CyTOF, were skewed towards the Th2 compartment, especially in typical IPEX.Elevated TSDR demethylated cells, combined with elevation of plasmatic and cellular markers of a polarized Type 2 inflammatory immune response extends our understanding of IPEX diagnosis and heterogeneity.IPEX-specific epigenetic and immunologic changes provide invaluable tools that, complementing the genetic diagnosis, allow monitoring disease progression and enable early treatment interventions.

    View details for DOI 10.1016/j.jaci.2022.09.013

    View details for PubMedID 36152823

  • Downregulation of SATB1 by miRNAs Reduces Megakaryocyte/Erythroid Progenitor Expansion in pre-clinical models of Diamond Blackfan Anemia. Experimental hematology Wilkes, M. C., Scanlon, V., Shibuya, A., Celika, A. M., Eskin, A., Chen, Z., Narla, A., Glader, B., Roncarolo, M. G., Nelson, S. F., Sakamoto, K. M. 2022

    Abstract

    Diamond Blackfan Anemia (DBA) is an inherited bone marrow failure syndrome that is associated with anemia, congenital anomalies, and cancer predisposition. It is categorized as a ribosomopathy, because over 80% or patients have haploinsufficiency of either a small or large subunit-associated ribosomal protein (RP). The erythroid pathology is predominantly due to a block and delay in early committed erythropoiesis with reduced Megakaryocyte/Erythroid Progenitors (MEPs). To understand the molecular pathways leading to pathogenesis of DBA, we performed RNA-seq on mRNA and miRNA from RPS19-deficient human hematopoietic stem and progenitor cells (HSPCs) and compared an existing database documenting transcript fluctuations across stages of early normal erythropoiesis. We determined the chromatin regulator, SATB1 was prematurely downregulated through the coordinated action of upregulated miR-34 and miR-30 during differentiation in ribosomal-insufficiency. Restoration of SATB1 rescued MEP expansion, leading to a modest improvement in erythroid and megakaryocyte expansion in RPS19-insufficiency. However, SATB1 expression did not impact expansion of committed erythroid progenitors, indicating ribosomal insufficiency impacts multiple stages during erythroid differentiation.

    View details for DOI 10.1016/j.exphem.2022.04.005

    View details for PubMedID 35460833

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