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.

doi:10.1101/2022.12.15.520650

bioRxiv · 10.1101/2022.12.15.520650

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.

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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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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.. 2022-12-18. Functional mRNA delivery to hematopoietic stem and progenitor cells in vivo.. https://doi.org/10.1101/2022.12.15.520650

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