In vivo hematopoietic stem cell modification by mRNA delivery

Hematopoietic stem cells (HSCs) are the source of all blood cells over an individual's lifetime. Diseased HSCs can be replaced with gene-engineered or healthy HSCs through HSC transplantation (HSCT). However, current protocols carry major side effects and have limited access. We developed CD117/LNP-messenger RNA (mRNA), a lipid nanoparticle (LNP) that encapsulates mRNA and is targeted to the stem cell factor receptor (CD117) on HSCs. Delivery of the anti-human CD117/LNP-based editing system yielded near-complete correction of hematopoietic sickle cells. Furthermore, in vivo delivery of pro-apoptotic PUMA (p53 up-regulated modulator of apoptosis) mRNA with CD117/LNP affected HSC function and permitted nongenotoxic conditioning for HSCT. The ability to target HSCs in vivo offers a nongenotoxic conditioning regimen for HSCT, and this platform could be the basis of in vivo genome editing to cure genetic disorders, which would abrogate the need for HSCT. Editor's summary Bone marrow stem cells are the source of all hematopoietic (blood) cells in the body. For patients with blood disorders, bone marrow transplantation with healthy donor marrow can be a highly successful therapy and can be curative for certain conditions. Breda et al . designed a strategy to reprogram bone marrow stem cells directly within the body without the need for donor cells or the use of potentially toxic conditioning regimens such as chemotherapy or radiation (see the Perspective by Ferrari and Naldini). Messenger RNA was delivered to bone marrow stem cells by intravenous injection in lipid nanoparticles, facilitating both gene editing and bone marrow transplantation. The ability to engineer bone marrow cells inside a patient without the need for traditional transplantation approaches could hold promise for a number of genetic disorders. —PNK Targeting specific messenger RNA-encapsulating lipid nanoparticles to hematopoietic stem cells permits in vivo bone marrow transplantation.