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Haploinsufficiency at the CX3CR1 locus of hematopoietic stem cells favors the appearance of microglia-like cells in the central nervous system of transplant recipients

Author

Listed:
  • Annita Montepeloso

    (Harvard Medical School
    Gene Therapy Consulting)

  • Davide Mattioli

    (Harvard Medical School
    University of Padua)

  • Danilo Pellin

    (Harvard Medical School)

  • Marco Peviani

    (Harvard Medical School)

  • Pietro Genovese

    (Harvard Medical School)

  • Alessandra Biffi

    (University of Padua)

Abstract

Transplantation of engineered hematopoietic stem/progenitor cells (HSPCs) showed curative potential in patients affected by neurometabolic diseases treated in early stage. Favoring the engraftment and maturation of the engineered HSPCs in the central nervous system (CNS) could allow enhancing further the therapeutic potential of this approach. Here we unveil that HSPCs haplo-insufficient at the Cx3cr1 (Cx3cr1−/+) locus are favored in central nervous system (CNS) engraftment and generation of microglia-like progeny cells (MLCs) as compared to wild type (Cx3cr1+/+) HSPCs upon transplantation in mice. Based on this evidence, we have developed a CRISPR-based targeted gene addition strategy at the human CX3CR1 locus resulting in an enhanced ability of the edited human HSPCs to generate mature MLCs upon transplantation in immunodeficient mice, and in lineage specific, regulated and robust transgene expression. This approach, which benefits from the modulation of pathways involved in microglia maturation and migration in haplo-insufficient cells, may broaden the application of HSPC gene therapy to a larger spectrum of neurometabolic and neurodegenerative diseases.

Suggested Citation

  • Annita Montepeloso & Davide Mattioli & Danilo Pellin & Marco Peviani & Pietro Genovese & Alessandra Biffi, 2024. "Haploinsufficiency at the CX3CR1 locus of hematopoietic stem cells favors the appearance of microglia-like cells in the central nervous system of transplant recipients," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-54515-4
    DOI: 10.1038/s41467-024-54515-4
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    References listed on IDEAS

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    1. Francesca Tucci & Stefania Galimberti & Luigi Naldini & Maria Grazia Valsecchi & Alessandro Aiuti, 2022. "A systematic review and meta-analysis of gene therapy with hematopoietic stem and progenitor cells for monogenic disorders," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    2. M. Kyle Cromer & Valentin V. Barsan & Erich Jaeger & Mengchi Wang & Jessica P. Hampton & Feng Chen & Drew Kennedy & Jenny Xiao & Irina Khrebtukova & Ana Granat & Tiffany Truong & Matthew H. Porteus, 2022. "Ultra-deep sequencing validates safety of CRISPR/Cas9 genome editing in human hematopoietic stem and progenitor cells," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
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