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Protein production is an early biomarker for RNA-targeted therapies.
Self, Wade K; Schoch, Kathleen M; Alex, Jacob; Barthélemy, Nicolas; Bollinger, James G; Sato, Chihiro; Cole, Tracy; Kordasiewicz, Holly B; Swayze, Eric; Bateman, Randall J; Miller, Timothy M.
Afiliação
  • Self WK; Department of Neurology Washington University School of Medicine St. Louis Missouri.
  • Schoch KM; Department of Neurology Washington University School of Medicine St. Louis Missouri.
  • Alex J; Department of Neurology Washington University School of Medicine St. Louis Missouri.
  • Barthélemy N; Department of Neurology Washington University School of Medicine St. Louis Missouri.
  • Bollinger JG; Department of Neurology Washington University School of Medicine St. Louis Missouri.
  • Sato C; Department of Neurology Washington University School of Medicine St. Louis Missouri.
  • Cole T; Ionis Pharmaceuticals Carlsbad California.
  • Kordasiewicz HB; Ionis Pharmaceuticals Carlsbad California.
  • Swayze E; Ionis Pharmaceuticals Carlsbad California.
  • Bateman RJ; Department of Neurology Washington University School of Medicine St. Louis Missouri.
  • Miller TM; Department of Neurology Washington University School of Medicine St. Louis Missouri.
Ann Clin Transl Neurol ; 5(12): 1492-1504, 2018 Dec.
Article em En | MEDLINE | ID: mdl-30564616
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.

Texto completo: 1 Base de dados: MEDLINE Idioma: En Ano de publicação: 2018 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Idioma: En Ano de publicação: 2018 Tipo de documento: Article