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

Rita Milazzo, Annita Montepeloso, Rajesh Kumar, Francesca Ferro, Eleonora Cavalca, Pietro Rigoni, Paolo Cabras, Yuri Ciervo, Sabyasachi Das, Alessia Capotondo, Danilo Pellin, Marco Peviani and Alessandra Biffi ()
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Rita Milazzo: University of Padua
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
Eleonora Cavalca: San Raffaele Scientific Institute
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
Alessandra Biffi: University of Padua

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-52301-w

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