Therapeutic efficacy of intracerebral hematopoietic stem cell gene therapy in an Alzheimer's disease mouse model.
Rita MilazzoAnnita MontepelosoRajesh KumarFrancesca FerroEleonora CavalcaPietro RigoniPaolo CabrasYuri CiervoSabyasachi DasAlessia CapotondoDanilo PellinMarco PevianiAlessandra BiffiPublished in: Nature communications (2024)
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.
Keyphrases
- hematopoietic stem cell
- blood brain barrier
- gene therapy
- cell therapy
- mouse model
- inflammatory response
- high fat diet induced
- induced apoptosis
- cognitive decline
- neuropathic pain
- single cell
- traumatic brain injury
- acute myeloid leukemia
- cell cycle arrest
- genome wide
- cognitive impairment
- cerebral ischemia
- gene expression
- copy number
- spinal cord
- dna methylation
- oxidative stress
- adipose tissue
- brain injury
- insulin resistance
- peripheral blood
- skeletal muscle
- replacement therapy