期刊
SCIENCE ADVANCES
卷 7, 期 3, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.aba1028
关键词
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资金
- Institute for Translational Medicine and Therapeutics (ITMAT) Transdisciplinary Program in Translational Medicine and Therapeutics
- U.S. National Institutes of Health (NIH) [DP2 TR002776, DP2HL152427]
- NIH [1R01DK123049-01]
- Burroughs Wellcome Fund Career Award at the Scientific Interface (CASI)
- NIH T32 training grant [T32HL007954]
- NIH NCI F32 fellowship [1F32CA24347-01A1]
- NIH NHLBI F32 fellowship [F32HL143861]
- Tau Beta Pi Fellowship
Using ionizable lipid nanoparticles, mRNA can be effectively and safely delivered to mouse fetuses to produce therapeutic secreted proteins, providing a platform for prenatal gene editing and protein replacement.
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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