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. 2024 May 7;15:3804. doi: 10.1038/s41467-024-47460-9

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© The Author(s) 2024

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 2 — a, b Pcca^−/− (A138T) mice received a single bolus IV dose of mRNA-3927 (1.0 or 2.0 mg/kg). Blood samples were collected at multiple time points up to 48 h postdose. Plasma concentrations of hPCCA (n = 4–7 mice/dose level/timepoint) and hPCCB mRNA (n = 4–7 mice/dose level/timepoint), respectively were quantified using branched DNA analysis. c Pcca^−/− (A138T) mice received 2 IV bolus doses of Tris-sucrose (control) or 0.5 mg/kg mRNA-3927 on Days 0 and 28 (n = 6 mice/group). PCC activity was measured using a radiometric activity assay wherein the mitochondrial fractions of liver homogenates were incubated with a PCC substrate and the enzymatic product was quantified by scintillation. d–f Blood was collected from mice prior to treatment and on Days 2, 8, 14, 22, and 28 after the first IV dose, and 2 days after the second IV dose. Plasma concentrations of 2-MC (n = 6 mice/group, where only n = 5 samples were available for analysis in the 0.5 mg/kg mRNA-3927 group at Day 8), 3-HP (n = 6 mice/group, where only n = 2 and 5 samples were available for analysis in the Wild type group at Days 2 and 22, respectively; where only n = 5 and 2 samples were available for analysis in the 0.5 mg/kg mRNA-3927 group prior to treatment and Day 8, respectively; where only n = 5 samples were available for analysis in the Control group at Day 2), and C3/C2 (n = 6 mice/group, where only n = 5 samples were available for analysis in the 0.5 mg/kg mRNA-3927 group at Days 8) were quantified by LC-MS/MS. Dotted lines represent dose administrations. 2-MC 2-methylcitrate, 3-HP 3-hydroxypropionate, C3/C2 ratio of propionylcarnitine to acetylcarnitine, hPCCA human propionyl-coenzyme A carboxylase α subunit, hPCCB human propionyl- coenzyme A carboxylase β subunit, IV intravenous, LC-MS/MS liquid chromatography-tandem mass spectrometry, mRNA messenger RNA, PCC propionyl- coenzyme A carboxylase, SD standard deviation. Source data are provided as a Source Data file.