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  • Rare immune diseases paving the road for genome editing-based precision medicine. Frontiers in genome editing Pavel-Dinu, M., Borna, S., Bacchetta, R. 2023; 5: 1114996


    Clustered regularly interspaced short palindromic repeats (CRISPR) genome editing platform heralds a new era of gene therapy. Innovative treatments for life-threatening monogenic diseases of the blood and immune system are transitioning from semi-random gene addition to precise modification of defective genes. As these therapies enter first-in-human clinical trials, their long-term safety and efficacy will inform the future generation of genome editing-based medicine. Here we discuss the significance of Inborn Errors of Immunity as disease prototypes for establishing and advancing precision medicine. We will review the feasibility of clustered regularly interspaced short palindromic repeats-based genome editing platforms to modify the DNA sequence of primary cells and describe two emerging genome editing approaches to treat RAG2 deficiency, a primary immunodeficiency, and FOXP3 deficiency, a primary immune regulatory disorder.

    View details for DOI 10.3389/fgeed.2023.1114996

    View details for PubMedID 36846437

  • 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


    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

  • Two is Better Than One: CRISPR/Cas9 Based Gene Editing with FOXP3 Isoforms for IPEX Therapy Lee, E., Borna, S., Sato, Y., Bacchetta, R., Roncarolo, M., Porteus, M. CELL PRESS. 2022: 34
  • Loss of Treg identity in IPEX patients is associated with increase autoreactivity in Teff cells Borna, S., Lee, E., Lakshmanan, U., Narula, M., Schulze, J., Ramachandran, A., Bertaina, A., Meffre, E., Maria, R., Bacchetta, R. SPRINGER/PLENUM PUBLISHERS. 2022: S78-S79
  • Towards gene therapy for IPEX syndrome. European journal of immunology Borna, S., Lee, E., Sato, Y., Bacchetta, R. 2022


    Immune dysregulation polyendocrinopathy enteropathy X linked (IPEX) syndrome is an uncurable disease of the immune system, with immune dysregulation that is caused by mutations in FOXP3. Current treatment options, such as pharmacological immune suppression and allogeneic hematopoietic stem cell transplantation, have been beneficial but present limitations, and their life-long consequences are ill defined. Other similar blood monogenic diseases have been successfully treated using gene transfer in autologous patient cells, thus providing an effective and less invasive therapeutic. Development of gene therapy for patients with IPEX is particularly challenging because successful strategies must restore the complex expression profile of the transcription factor FOXP3, ensuring it is tightly regulated, and its cell subset-specific roles are maintained. This review summarizes current efforts toward achieving gene therapy to treat the immune dysregulation in IPEX patients. This article is protected by copyright. All rights reserved.

    View details for DOI 10.1002/eji.202149210

    View details for PubMedID 35355253