@article{32b06d53dc264f30a26eb524333ec2d0,
title = "Protein production is an early biomarker for RNA-targeted therapies",
abstract = "Objectives: Clinical trials for progressive neurodegenerative disorders such as Alzheimer's Disease and Amyotrophic Lateral Sclerosis have been hindered due to the absence of effective pharmacodynamics markers to assay target engagement. We tested whether measurements of new protein production would be a viable pharmacodynamics tool for RNA-targeted therapies. Methods: Transgenic animal models expressing human proteins implicated in neurodegenerative disorders – microtubule-associated protein tau (hTau) or superoxide dismutase-1 (hSOD1) – were treated with antisense oligonucleotides (ASOs) delivered to the central nervous system to target these human mRNA transcripts. Simultaneously, animals were administered 13C6-leucine via drinking water to measure new protein synthesis after ASO treatment. Measures of new protein synthesis and protein concentration were assayed at designated time points after ASO treatment using targeted proteomics. Results: ASO treatment lowered hTau mRNA and protein production (measured by 13C6-leucine-labeled hTau protein) earlier than total hTau protein concentration in transgenic mouse cortex. In the CSF of hSOD1 transgenic rats, ASO treatment lowered newly generated hSOD1 protein driven by decreases in newly synthesized hSOD1 protein, not overall protein concentration, 30 days after treatment. At later time points, decreases in newly generated protein were still observed after mRNA lowering reached a steady state after ASO treatment. Interpretation: Measures of newly generated protein show earlier pharmacodynamics changes for RNA-lowering therapeutics compared with total protein concentration. Early in ASO treatment, decreases in newly generated protein are driven by changes in newly synthesized protein. Measuring new protein production in CSF may be a promising early pharmacodynamics marker for RNA-targeted therapeutics.",
author = "Self, {Wade K.} and Schoch, {Kathleen M.} and Jacob Alex and Nicolas Barth{\'e}lemy and Bollinger, {James G.} and Chihiro Sato and Tracy Cole and Kordasiewicz, {Holly B.} and Eric Swayze and Bateman, {Randall J.} and Miller, {Timothy M.}",
note = "Funding Information: We thank Drs. Cheryl Frankfater and John Turk of the Biomedical Mass Spectrometry Core at Washington University in St. Louis for assistance with gas chromatography-mass spectrometry analysis. Research reported in this publication was supported by the Washington University Institute of Clinical and Translational Sciences grant UL1TR002345, sub-award TL1TR002344 from the National Center for Advancing Translational Sciences (NCATS), the National Institute of Neurological Disorders and Stroke grant U01NS084870, grant R01NS098716 (TM Miller, PI) and R01NS095773 (RJ Bateman, PI) from the National Institutes of Health, as well as the MetLife Foundation Award (RJ Bateman, PI) (NIH). The content is solely the responsibility of the authors and does not necessarily represent the official view of NIH. Funding Information: Research reported in this publication was supported by the Washington University Institute of Clinical and Translational Sciences grant UL1TR002345, sub-award TL1TR002344 from the National Center for Advancing Translational Sciences (NCATS), the National Institute of Neurological Disorders and Stroke grant U01NS084870, grant R01NS098716 (TM Miller, PI), and R01NS095773 (RJ Bateman, PI) from the National Institutes of Health, as well as the MetLife Foundation Award (RJ Bateman, PI) (NIH). The content is solely the responsibility of the authors and does not necessarily represent the official view of NIH. Funding Information: grant UL1TR002345, sub-award TL1TR002344 from the National Center for Advancing Translational Sciences (NCATS), the National Institute of Neurological Disorders and Stroke grant U01NS084870, grant R01NS098716 (TM Miller, PI) and R01NS095773 (RJ Bateman, PI) from the National Institutes of Health, as well as the MetLife Foundation Award (RJ Bateman, PI) (NIH). The content is solely the responsibility of the authors and does not necessarily represent the official view of NIH. Publisher Copyright: {\textcopyright} 2018 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.",
year = "2018",
month = dec,
doi = "10.1002/acn3.657",
language = "English",
volume = "5",
pages = "1492--1504",
journal = "Annals of Clinical and Translational Neurology",
issn = "2328-9503",
number = "12",
}