Functional mRNA delivery to hematopoietic stem and progenitor cells in vivo.
Alvarez, D.; Masse-Ranson, G.; Sedimbi, S. K.; Wisti, P.; Rodriguez, L.; Santana, J.; Manning, T.; Towner, T.; Geilich, B.; Mihai, C.; Mishra, A.; Gurumurthy, S.; Frederick, J.; von Andrian, U. H.; Hoggatt, J.; Moore, M. J.; Mora, J. R.
Show abstract
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. One-Sentence SummaryLNP can deliver functional mRNA to mouse, non-human primate, and human HSC.
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