Riley Rachel S, Kashyap Meghana V, Billingsley Margaret M, White Brandon, Alameh Mohamad-Gabriel, Bose Sourav K, Zoltick Philip W, Li Hiaying, Zhang Rui, Cheng Andrew Y, Weissman Drew, Peranteau William H, Mitchell Michael J
Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA.
The Center for Fetal Research, Division of General, Thoracic, and Fetal Surgery, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Sci Adv. 2021 Jan 13;7(3). doi: 10.1126/sciadv.aba1028. Print 2021 Jan.
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.
临床进展使得能够对一些遗传疾病进行产前诊断，这些疾病是基因和酶疗法（如信使核糖核酸（mRNA）介导的蛋白质替代疗法）的候选对象。由于胎儿体积小、免疫系统不成熟以及祖细胞丰富，产前mRNA疗法能够在不可逆病变发生之前治疗疾病，且具有高治疗效果和安全性。然而，用于产前递送的非病毒平台的开发尚处于起步阶段。我们开发了一个可电离脂质纳米颗粒（LNP）文库，用于在子宫内将mRNA递送至小鼠胎儿。我们筛选了用于递送荧光素酶mRNA的LNP，并确定了与基准递送系统DLin-MC3-DMA和jetPEI相比，能更高效、安全地在胎儿肝脏、肺和肠道中积累的制剂。我们证明LNP可以递送mRNA以诱导肝脏产生治疗性分泌蛋白。这些LNP可能为子宫内mRNA递送用于蛋白质替代和基因编辑提供一个平台。
