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Clustered regularly interspaced short palindromic repeats/Cas9-mediated gene editing. A promising strategy in hematological disorders

  • Author Footnotes
    ⁎ These authors contributed equally to this work.
    Laura Ugalde
    Footnotes
    ⁎ These authors contributed equally to this work.
    Affiliations
    Biomedical Innovation Unit, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT), Madrid, Spain

    Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain

    Instituto de Investigaciones Sanitarias Fundación Jiménez Díaz (IIS-FJD), Madrid, Spain
    Search for articles by this author
  • Author Footnotes
    ⁎ These authors contributed equally to this work.
    Sara Fañanas
    Footnotes
    ⁎ These authors contributed equally to this work.
    Affiliations
    Biomedical Innovation Unit, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT), Madrid, Spain

    Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain

    Instituto de Investigaciones Sanitarias Fundación Jiménez Díaz (IIS-FJD), Madrid, Spain
    Search for articles by this author
  • Raúl Torres
    Correspondence
    Correspondence: Raúl Torres, Oscar Quintana-Bustamante, and Paula Río, CIEMAT, Division of Hematopoietic Innovative Therapies, Av. Complutense 40, 28040 Madrid, Spain.
    Affiliations
    Biomedical Innovation Unit, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT), Madrid, Spain

    Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain

    Instituto de Investigaciones Sanitarias Fundación Jiménez Díaz (IIS-FJD), Madrid, Spain

    Molecular Cytogenetics Group, Human Cancer Genetics Program, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain
    Search for articles by this author
  • Oscar Quintana-Bustamante
    Correspondence
    Correspondence: Raúl Torres, Oscar Quintana-Bustamante, and Paula Río, CIEMAT, Division of Hematopoietic Innovative Therapies, Av. Complutense 40, 28040 Madrid, Spain.
    Affiliations
    Biomedical Innovation Unit, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT), Madrid, Spain

    Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain

    Instituto de Investigaciones Sanitarias Fundación Jiménez Díaz (IIS-FJD), Madrid, Spain
    Search for articles by this author
  • Paula Río
    Correspondence
    Correspondence: Raúl Torres, Oscar Quintana-Bustamante, and Paula Río, CIEMAT, Division of Hematopoietic Innovative Therapies, Av. Complutense 40, 28040 Madrid, Spain.
    Affiliations
    Biomedical Innovation Unit, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT), Madrid, Spain

    Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain

    Instituto de Investigaciones Sanitarias Fundación Jiménez Díaz (IIS-FJD), Madrid, Spain
    Search for articles by this author
  • Author Footnotes
    ⁎ These authors contributed equally to this work.
Published:January 05, 2023DOI:https://doi.org/10.1016/j.jcyt.2022.11.014

      Abstract

      The clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 system has revolutionized the gene editing field, making it possible to interrupt, insert or replace a sequence of interest with high precision in the human genome. Its easy design and wide applicability open up a variety of therapeutic alternatives for the treatment of genetic diseases. Indeed, very promising approaches for the correction of hematological disorders have been developed in the recent years, based on the self-renewal and multipotent differentiation properties of hematopoietic stem and progenitor cells, which make this cell subset the ideal target for gene therapy purposes. This technology has been applied in different congenital blood disorders, such as primary immunodeficiencies, X-linked severe combined immunodeficiency, X-linked chronic granulomatous disease or Wiskott–Aldrich syndrome, and inherited bone marrow failure syndromes, such as Fanconi anemia, congenital amegakaryocytic thrombocytopenia or severe congenital neutropenia. Furthermore, CRISPR/Cas9-based gene editing has been implemented successfully as a novel therapy for cancer immunotherapy, by the development of promising strategies such as the use of oncolytic viruses or adoptive cellular therapy to the chimeric antigen receptor–T-cell therapy. Therefore, considering the variety of genes and mutations affected, we can take advantage of the different DNA repair mechanisms by CRISPR/Cas9 in different manners, from homology-directed repair to non-homologous-end-joining to the latest emerging technologies such as base and prime editing. Although the delivery systems into hematopoietic stem and progenitor cells are still the bottleneck of this technology, some of the advances in genome editing shown in this review have already reached a clinical stage and show very promising preliminary results.

      Key Words

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