Bone-marrow-homing lipid nanoparticles for genome editing in diseased and malignant haematopoietic stem cells
Menée in vitro et à l'aide de modèles murins, cette étude met en évidence l'intérêt de nanoparticules lipidiques chargées en ARN messagers d'enzymes spécifiques (Cas9 ou recombinase Cre) pour modifier génétiquement les cellules souches hématopoïétiques leucémiques au niveau de la moelle osseuse
Therapeutic genome editing of haematopoietic stem cells (HSCs) would provide long-lasting treatments for multiple diseases. However, the in vivo delivery of genetic medicines to HSCs remains challenging, especially in diseased and malignant settings. Here we report on a series of bone-marrow-homing lipid nanoparticles that deliver mRNA to a broad group of at least 14 unique cell types in the bone marrow, including healthy and diseased HSCs, leukaemic stem cells, B cells, T cells, macrophages and leukaemia cells. CRISPR/Cas and base editing is achieved in a mouse model expressing human sickle cell disease phenotypes for potential foetal haemoglobin reactivation and conversion from sickle to non-sickle alleles. Bone-marrow-homing lipid nanoparticles were also able to achieve Cre-recombinase-mediated genetic deletion in bone-marrow-engrafted leukaemic stem cells and leukaemia cells. We show evidence that diverse cell types in the bone marrow niche can be edited using bone-marrow-homing lipid nanoparticles.
Nature Nanotechnology , résumé, 2024