ObjectivesClinical 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.MethodsTransgenic 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.InterpretationMeasures 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.

Coxsackie B infections can have varying clinical presentations. Necrotizing myopathy and rhabdomyolysis with remarkably high creatine phosphokinase levels is a rare complication associated with high morbidity and mortality. A 28-year-old male presented with complaints of weakness, body aches, and decreased urine output. Initial lab work showed a creatine phosphokinase level estimated at 5,366,100 U/l. Initial Coxsackie B4 titers were at 1:160. Muscle biopsy of the right calf revealed necrotizing myopathy consistent with viral myopathy. This case highlights Coxsackie B4 as a potential pathogen that can cause extensive muscle necrosis producing extreme creatine phosphokinase levels leading to rhabdomyolysis. Taking a comprehensive history is essential to identify viral prodromal symptoms to guide broader serological testing for uncommon viral species.

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