Ionizable lipid nanoparticles for in utero mRNA delivery

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Abstract

Lipid nanoparticles deliver mRNA to mouse fetuses, which may ultimately enable in utero therapy to treat fetal genetic diseases.

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.

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Author and article information

Journal

Journal ID (nlm-ta): Sci Adv

Journal ID (iso-abbrev): Sci Adv

Journal ID (publisher-id): SciAdv

Journal ID (hwp): advances

Title: Science Advances

Publisher: American Association for the Advancement of Science

ISSN (Electronic): 2375-2548

Publication date Collection: January 2021

Publication date (Electronic): 13 January 2021

Volume: 7

Issue: 3

Electronic Location Identifier: eaba1028

Affiliations

[1 ]Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA.

[2 ]The Center for Fetal Research, Division of General, Thoracic, and Fetal Surgery, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA.

[3 ]Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

[4 ]Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

[5 ]Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

[6 ]Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

[7 ]Institute for Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

Author notes

[*]

These authors contributed equally to this work.

[† ]Corresponding author. Email: peranteauw@ 123456email.chop.edu (W.H.P.); mjmitch@ 123456seas.upenn.edu (M.J.M.)

Author information

Rachel S. Riley http://orcid.org/0000-0002-3267-5403

Meghana V. Kashyap http://orcid.org/0000-0002-7920-983X

Margaret M. Billingsley http://orcid.org/0000-0003-4499-9066

Brandon White http://orcid.org/0000-0002-5873-8011

Hiaying Li http://orcid.org/0000-0002-3522-6582

Andrew Y. Cheng http://orcid.org/0000-0002-1596-8458

Drew Weissman http://orcid.org/0000-0002-1501-6510

William H. Peranteau http://orcid.org/0000-0003-1608-861X

Michael J. Mitchell http://orcid.org/0000-0002-3628-2244

Article

Publisher ID: aba1028

DOI: 10.1126/sciadv.aba1028

PMC ID: 7806221

PubMed ID: 33523869

SO-VID: faa9c6af-ecc9-4448-bfdb-a1bb6790b2f8

Copyright © Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.