Open AccessProtein production is an early biomarker for RNA ‐targeted therapies
Author(s) -
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.
Publication year - 2018
Publication title -
annals of clinical and translational neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.824
H-Index - 42
ISSN - 2328-9503
DOI - 10.1002/acn3.657
Subject(s) - messenger rna , protein biosynthesis , medicine , biomarker , rna , pharmacodynamics , protein aggregation , pharmacology , proteomics , transgene , genetically modified mouse , microbiology and biotechnology , biology , biochemistry , pharmacokinetics , gene
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 ( hT au) or superoxide dismutase‐1 ( hSOD 1) – were treated with antisense oligonucleotides ( ASO s) delivered to the central nervous system to target these human mRNA transcripts. Simultaneously, animals were administered 13 C 6 ‐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 hT au mRNA and protein production (measured by 13 C 6 ‐leucine‐labeled hT au protein) earlier than total hT au protein concentration in transgenic mouse cortex. In the CSF of hSOD 1 transgenic rats, ASO treatment lowered newly generated hSOD 1 protein driven by decreases in newly synthesized hSOD 1 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.