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.
In utero base editing has the potential to correct disease-causing mutations before the onset of pathology. Mucopolysaccharidosis type I (MPS-IH, Hurler syndrome) is a lysosomal storage disease (LSD) affecting multiple organs, often leading to early postnatal cardiopulmonary demise. We assessed in utero adeno-associated virus serotype 9 (AAV9) delivery of an adenine base editor (ABE) targeting the Idua G→A (W392X) mutation in the MPS-IH mouse, corresponding to the common IDUA G→A (W402X) mutation in MPS-IH patients. Here we show efficient long-term W392X correction in hepatocytes and cardiomyocytes and low-level editing in the brain. In utero editing was associated with improved survival and amelioration of metabolic, musculoskeletal, and cardiac disease. This proof-of-concept study demonstrates the possibility of efficiently performing therapeutic base editing in multiple organs before birth via a clinically relevant delivery mechanism, highlighting the potential of this approach for MPS-IH and other genetic diseases.
Field studies were established on the alluvial floodplain soils in Louisiana, from 2013 to 2015, to evaluate the effect of silicate slag applications on productivity of wheat (Triticum aestivum), under sufficient and high nitrogen (N) application rates. Treatments were arranged in a randomized complete block design, with four replications consisting of twelve treatments: a factorial combination of two N (101 and 145 kg N ha−1) and five silicate slag rates (0, 1, 2, 4.5, and 9 Mg ha−1), and two control plots (with and without lime). Nitrogen had a greater impact on wheat productivity than silicate slag application. Wheat grain yield reached over 7000 kg ha−1 with applications of 145 kg N, and 9 Mg silicate slag per ha for soil having Si level <20 mg kg−1. Yield increases due to N or Si were attributed to the increase in number of spike m−2 and grain number spike−1. Silicate slag application effectively raised soil pH, and availability of several plant-essential nutrients, including plant-available N (nitrate, NO3−), demonstrating the benefits of slag application are beyond increasing plant-available Si. The benefits of silicate slag application were clearly observed in wheat supplied with high N, and on soil with low plant-available Si.
Background:We previously showed that the supraorbital ethmoid cell (SOEC) is a reliable landmark for identifying the anterior ethmoid artery (AEA). Recent data have suggested that Keros classification is also a dependable predictor. We aim to characterize the location of the AEA and its relation to the skull base in patients with and without SOEC using the Keros classification.
Methods:Retrospective radiographic evaluation of computed tomography (CT) scans of 76 patients (40 with SOEC, 36 without) was conducted. Distance of AEA from skull base and prevalence of AEA outside of the skull base were measured on each side and compared between groups using the 2-sample t test and χ 2 test, respectively. Subgroup analysis was carried out based on the Keros classification.Results: Mean distance of AEA from the skull base was 1.32 ± 1.5 mm in patients with SOEC and 0.47 ± 1.08 mm in those without (p < 0.001). Prevalence of AEA outside of the skull base was 53.8% in those with SOEC and 18.1% in those without (p < 0.001). Comparing patients with SOEC to those without, AEA was found below the skull base in 30% vs 0% of cases with Keros type 1 (p = 0.45), 58% vs 14.5% with Keros type 2 (p < 0.001), and 60% vs 50% with Keros type 3 (p = 0.72).
Conclusion:The presence of SOEC is associated with a higher prevalence of the AEA coursing below the level of the skull base in all Keros types, thus placing the artery at greater risk for injury. Careful surgical planning is needed to avoid potential orbital complications. C 2019 ARS-AAOA, LLC.
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