Gene-therapy research is making steady progress on an array of blood-cell diseases, including immunodeficiencies, sickle cell disease and thalassemia. These programs may use gene transfer or gene editing, but all of them require engineering of patients’ hematopoietic stem cells (HSCs) in the laboratory. In an arduous procedure modeled on stem cell transplants for cancer, HSCs are mobilized from the bone marrow into the blood, harvested, genetically engineered, and infused back into the patient. Myelosuppressive conditioning is given to ‘make space’ for the graft in the bone marrow, increasing the risk of infections and other complications. HSC gene therapies have been administered to hundreds of patients, but these complex, costly procedures are unavailable to millions of people worldwide who could benefit from them. A recent study in Science by Breda et al. describes an approach that would radically simplify HSC gene therapy by genetically modifying the cells in vivo.
Breda et al. capitalize on the technology behind the COVID-19 mRNA vaccines, which allows delivery of proteins in the form of mRNA encapsulated in lipid nanoparticles (LNPs). To redirect LNPs from the liver to HSCs, the authors conjugate them to antibodies against CD117, a cell-surface receptor on HSCs. Using mRNA encoding Cre recombinase, they find that intravenous injection of mRNA-LNPs in reporter mice leads to dose-dependent editing of long term–repopulating HSCs at efficiencies greater than 50%. In another experiment with a more clinically relevant editing enzyme, they correct a sickle-cell mutation in human cells in vitro with mRNA-LNPs carrying a CRISPR adenine base editor and guide RNA. If the approach proves safe and effective in humans, it could provide an alternative and more scalable route to HSC gene editing.
This is a preview of subscription content, access via your institution