2. Academic Validation
  3. Ionizable lipid nanoparticles for in utero mRNA delivery

Ionizable lipid nanoparticles for in utero mRNA delivery

  • Sci Adv. 2021 Jan 13;7(3):eaba1028. doi: 10.1126/sciadv.aba1028.
Rachel S Riley 1,  Meghana V Kashyap 2,  Margaret M Billingsley 1,  Brandon White 2,  Mohamad-Gabriel Alameh 3,  Sourav K Bose 2,  Philip W Zoltick 2,  Hiaying Li 2,  Rui Zhang 1,  Andrew Y Cheng 2,  Drew Weissman 3,  William H Peranteau 4,  Michael J Mitchell 5 6 7 8 9
Affiliations

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 The Center for Fetal Research, Division of General, Thoracic, and Fetal Surgery, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. [email protected] [email protected].
  • 5 Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA. [email protected] [email protected].
  • 6 Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 7 Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 8 Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 9 Institute for Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
PMID: 33523869 DOI: 10.1126/sciadv.aba1028
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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