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Therapeutic efficacy of intracerebral hematopoietic stem cell gene therapy in an Alzheimer’s disease mouse model

Author

Listed:
  • Rita Milazzo

    (University of Padua
    San Raffaele Scientific Institute)

  • Annita Montepeloso

    (Dana-Farber/Boston Children’s Cancer and Blood Disorders Center)

  • Rajesh Kumar

    (Dana-Farber/Boston Children’s Cancer and Blood Disorders Center)

  • Francesca Ferro

    (San Raffaele Scientific Institute
    Dana-Farber/Boston Children’s Cancer and Blood Disorders Center)

  • Eleonora Cavalca

    (San Raffaele Scientific Institute
    Dana-Farber/Boston Children’s Cancer and Blood Disorders Center)

  • Pietro Rigoni

    (University of Padua)

  • Paolo Cabras

    (University of Pavia)

  • Yuri Ciervo

    (University of Padua)

  • Sabyasachi Das

    (Dana-Farber/Boston Children’s Cancer and Blood Disorders Center)

  • Alessia Capotondo

    (San Raffaele Scientific Institute)

  • Danilo Pellin

    (Dana-Farber/Boston Children’s Cancer and Blood Disorders Center)

  • Marco Peviani

    (Dana-Farber/Boston Children’s Cancer and Blood Disorders Center
    University of Pavia)

  • Alessandra Biffi

    (University of Padua
    San Raffaele Scientific Institute
    Dana-Farber/Boston Children’s Cancer and Blood Disorders Center)

Abstract

The conditions supporting the generation of microglia-like cells in the central nervous system (CNS) after transplantation of hematopoietic stem/progenitor cells (HSPC) have been studied to advance the treatment of neurodegenerative disorders. Here, we explored the transplantation efficacy of different cell subsets and delivery routes with the goal of favoring the establishment of a stable and exclusive engraftment of HSPCs and their progeny in the CNS of female mice. In this setting, we show that the CNS environment drives the expansion, distribution and myeloid differentiation of the locally transplanted cells towards a microglia-like phenotype. Intra-CNS transplantation of HSPCs engineered to overexpress TREM2 decreased neuroinflammation, Aβ aggregation and improved memory in 5xFAD female mice. Our proof of concept study demonstrates the therapeutic potential of HSPC gene therapy for Alzheimer’s disease.

Suggested Citation

  • Rita Milazzo & Annita Montepeloso & Rajesh Kumar & Francesca Ferro & Eleonora Cavalca & Pietro Rigoni & Paolo Cabras & Yuri Ciervo & Sabyasachi Das & Alessia Capotondo & Danilo Pellin & Marco Peviani , 2024. "Therapeutic efficacy of intracerebral hematopoietic stem cell gene therapy in an Alzheimer’s disease mouse model," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-52301-w
    DOI: 10.1038/s41467-024-52301-w
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    References listed on IDEAS

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    1. Harald Lund & Melanie Pieber & Roham Parsa & Jinming Han & David Grommisch & Ewoud Ewing & Lara Kular & Maria Needhamsen & Alexander Espinosa & Emma Nilsson & Anna K. Överby & Oleg Butovsky & Maja Jag, 2018. "Competitive repopulation of an empty microglial niche yields functionally distinct subsets of microglia-like cells," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
    2. Ranjie Xu & Xiaoxi Li & Andrew J. Boreland & Anthony Posyton & Kelvin Kwan & Ronald P. Hart & Peng Jiang, 2020. "Human iPSC-derived mature microglia retain their identity and functionally integrate in the chimeric mouse brain," Nature Communications, Nature, vol. 11(1), pages 1-16, December.
    3. Anat Shemer & Jonathan Grozovski & Tuan Leng Tay & Jenhan Tao & Alon Volaski & Patrick Süß & Alberto Ardura-Fabregat & Mor Gross-Vered & Jung-Seok Kim & Eyal David & Louise Chappell-Maor & Lars Thiele, 2018. "Engrafted parenchymal brain macrophages differ from microglia in transcriptome, chromatin landscape and response to challenge," Nature Communications, Nature, vol. 9(1), pages 1-16, December.
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