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

被引：1

作者：

Milazzo, Rita ^{[1
,2
]}

Montepeloso, Annita ^{[3
]}

Kumar, Rajesh ^{[3
]}

Ferro, Francesca ^{[2
,3
]}

Cavalca, Eleonora ^{[2
,3
]}

Rigoni, Pietro ^{[1
]}

Cabras, Paolo ^{[4
]}

Ciervo, Yuri ^{[1
]}

Das, Sabyasachi ^{[3
]}

Capotondo, Alessia ^{[2
]}

Pellin, Danilo ^{[3
]}

Peviani, Marco ^{[3
,4
]}

Biffi, Alessandra ^{[1
,2
,3
]}

机构：

[1] Univ Padua, Dept Women & Childs Hlth, Div Hematol Oncol & Stem Cell Transplantat, Padua, Italy

[2] Ist Sci San Raffaele, San Raffaele Telethon Inst Gene Therapy, Div Regenerat Med Stem Cell & Gene Therapy, Milan, Italy

[3] Dana Farber Boston Childrens Canc & Blood Disorder, Gene Therapy Program, Boston, MA 02115 USA

[4] Univ Pavia, Dept Biol & Biotechnol L Spallanzani, Cellular & Mol Neuropharmacol Lab, Pavia, Italy

来源：

NATURE COMMUNICATIONS | 2024年 / 15卷 / 01期

基金：

欧洲研究理事会;

关键词：

METACHROMATIC LEUKODYSTROPHY; MICROGLIA; BRAIN; EXPRESSION; NEURODEGENERATION; TRANSPLANTATION; TRAFFICKING; PHENOTYPE; DELIVERY; REVEALS;

D O I：

10.1038/s41467-024-52301-w

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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, A beta 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. This study aims at enhancing hematopoietic stem cell (HSC) gene therapy potential to treat neurodegenerative diseases via innovative approaches. Findings demonstrate the therapeutic benefits of intracerebral transplantation of TREM2-engineered HSCs in an Alzheimer's disease mouse model.

引用

页数：20

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