Functional mRNA delivery to hematopoietic stem and progenitor cells in vivo.

Gene correction of hematopoietic stem cells (HSC) is a promising therapeutic approach for multiple disorders. Current methods, however, require HSC collection from patients, gene correction during ex vivo culture, and re-infusion of corrected HSC into patients conditioned with chemotherapeutic agents. These approaches are complex, and the conditioning creates toxicities. We show that a lipid nanoparticle (LNP) can deliver mRNA encoding a reporter or a gene editing protein to HSC, with one injection transfecting ~25% of mouse HSC, and repeated doses resulting in higher editing efficiencies. We also demonstrate LNP-driven in vivo mRNA delivery to HSC in non-human primates and humanized mice. These results demonstrate a translatable approach to deliver mRNA encoding therapeutic proteins, or gene correcting tools, to HSC that do not require cell culture or toxic conditioning. ### Competing Interest Statement D.A., G.M-R., S.K.S., P.W., L.R., J.S., T.M., T.T., B.G., C.M., A.M., S.G., J.F., J.H., M.J.M. and J.R.M are employed by Moderna Inc. and hold equities from the company.