Ionizable lipid nanoparticles for in utero mRNA delivery

Rachel S. Riley; Meghana V. Kashyap; Margaret M. Billingsley; Brandon White; Mohamad Gabriel Alameh; Sourav K. Bose; Philip W. Zoltick; Hiaying Li; Rui Zhang; Andrew Y. Cheng; Drew Weissman; William H. Peranteau; Michael J. Mitchell

doi:10.1126/sciadv.aba1028

Ionizable lipid nanoparticles for in utero mRNA delivery

Rachel S. Riley, Meghana V. Kashyap, Margaret M. Billingsley, Brandon White, Mohamad Gabriel Alameh, Sourav K. Bose, Philip W. Zoltick, Hiaying Li, Rui Zhang, Andrew Y. Cheng, Drew Weissman, William H. Peranteau, Michael J. Mitchell

Research output: Contribution to journal › Article › peer-review

125 Scopus citations

Abstract

Clinical advances enable the prenatal diagnosis of genetic diseases that are candidates for gene and enzyme therapies such as messenger RNA (mRNA)-mediated protein replacement. Prenatal mRNA therapies can treat disease before the onset of irreversible pathology with high therapeutic efficacy and safety due to the small fetal size, immature immune system, and abundance of progenitor cells. However, the development of nonviral platforms for prenatal delivery is nascent. We developed a library of ionizable lipid nanoparticles (LNPs) for in utero mRNA delivery to mouse fetuses. We screened LNPs for luciferase mRNA delivery and identified formulations that accumulate within fetal livers, lungs, and intestines with higher efficiency and safety compared to benchmark delivery systems, DLin-MC3-DMA and jetPEI. We demonstrate that LNPs can deliver mRNAs to induce hepatic production of therapeutic secreted proteins. These LNPs may provide a platform for in utero mRNA delivery for protein replacement and gene editing.

Original language	English (US)
Article number	eaba1028
Journal	Science advances
Volume	7
Issue number	3
DOIs	https://doi.org/10.1126/sciadv.aba1028
State	Published - Jan 13 2021
Externally published	Yes

All Science Journal Classification (ASJC) codes

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title = "Ionizable lipid nanoparticles for in utero mRNA delivery",

abstract = "Clinical advances enable the prenatal diagnosis of genetic diseases that are candidates for gene and enzyme therapies such as messenger RNA (mRNA)-mediated protein replacement. Prenatal mRNA therapies can treat disease before the onset of irreversible pathology with high therapeutic efficacy and safety due to the small fetal size, immature immune system, and abundance of progenitor cells. However, the development of nonviral platforms for prenatal delivery is nascent. We developed a library of ionizable lipid nanoparticles (LNPs) for in utero mRNA delivery to mouse fetuses. We screened LNPs for luciferase mRNA delivery and identified formulations that accumulate within fetal livers, lungs, and intestines with higher efficiency and safety compared to benchmark delivery systems, DLin-MC3-DMA and jetPEI. We demonstrate that LNPs can deliver mRNAs to induce hepatic production of therapeutic secreted proteins. These LNPs may provide a platform for in utero mRNA delivery for protein replacement and gene editing.",

author = "Riley, {Rachel S.} and Kashyap, {Meghana V.} and Billingsley, {Margaret M.} and Brandon White and Alameh, {Mohamad Gabriel} and Bose, {Sourav K.} and Zoltick, {Philip W.} and Hiaying Li and Rui Zhang and Cheng, {Andrew Y.} and Drew Weissman and Peranteau, {William H.} and Mitchell, {Michael J.}",

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doi = "10.1126/sciadv.aba1028",

language = "English (US)",

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AU - Riley, Rachel S.

AU - Kashyap, Meghana V.

AU - Billingsley, Margaret M.

AU - White, Brandon

AU - Alameh, Mohamad Gabriel

AU - Bose, Sourav K.

AU - Zoltick, Philip W.

AU - Li, Hiaying

AU - Zhang, Rui

AU - Cheng, Andrew Y.

AU - Weissman, Drew

AU - Peranteau, William H.

AU - Mitchell, Michael J.

PY - 2021/1/13

Y1 - 2021/1/13

N2 - Clinical advances enable the prenatal diagnosis of genetic diseases that are candidates for gene and enzyme therapies such as messenger RNA (mRNA)-mediated protein replacement. Prenatal mRNA therapies can treat disease before the onset of irreversible pathology with high therapeutic efficacy and safety due to the small fetal size, immature immune system, and abundance of progenitor cells. However, the development of nonviral platforms for prenatal delivery is nascent. We developed a library of ionizable lipid nanoparticles (LNPs) for in utero mRNA delivery to mouse fetuses. We screened LNPs for luciferase mRNA delivery and identified formulations that accumulate within fetal livers, lungs, and intestines with higher efficiency and safety compared to benchmark delivery systems, DLin-MC3-DMA and jetPEI. We demonstrate that LNPs can deliver mRNAs to induce hepatic production of therapeutic secreted proteins. These LNPs may provide a platform for in utero mRNA delivery for protein replacement and gene editing.

AB - Clinical advances enable the prenatal diagnosis of genetic diseases that are candidates for gene and enzyme therapies such as messenger RNA (mRNA)-mediated protein replacement. Prenatal mRNA therapies can treat disease before the onset of irreversible pathology with high therapeutic efficacy and safety due to the small fetal size, immature immune system, and abundance of progenitor cells. However, the development of nonviral platforms for prenatal delivery is nascent. We developed a library of ionizable lipid nanoparticles (LNPs) for in utero mRNA delivery to mouse fetuses. We screened LNPs for luciferase mRNA delivery and identified formulations that accumulate within fetal livers, lungs, and intestines with higher efficiency and safety compared to benchmark delivery systems, DLin-MC3-DMA and jetPEI. We demonstrate that LNPs can deliver mRNAs to induce hepatic production of therapeutic secreted proteins. These LNPs may provide a platform for in utero mRNA delivery for protein replacement and gene editing.

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Ionizable lipid nanoparticles for in utero mRNA delivery

Abstract

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