In vivo kinetic approach reveals slow SOD1 turnover in the CNS

Crisp, Matthew J.; Mawuenyega, Kwasi G.; Patterson, Bruce W.; Reddy, Naveen C.; Chott, Robert; Self, Wade; Weihl, Conrad C.; Jockel-Balsarotti, Jennifer; Varadhachary, Arun S.; Bucelli, Robert C.; Yarasheski, Kevin E.; Bateman, Randall J.; Miller, Timothy M.

doi:10.1172/jci80705

Cited by 55 publications

(67 citation statements)

References 41 publications

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“…The amount of 13 C 6 ‐Leucine found in plasma, the precursor for leucine found in the central nervous system,24 was consistent in all experiments between groups (Figure S1). …”

Section: Methodssupporting

confidence: 69%

“…In previous experiments, the G93A SOD1 rat model was used to demonstrate hSOD1 protein lowering after ASO treatment 42 days after treatment 26. Our group 24 and others 39 have shown that mutant hSOD1 exhibits a shorter protein half‐life in the CNS and CSF compared to WT hSOD1. Taken together, these data suggest that CSF WT hSOD1 protein concentration will occur at an even later time point than 50 days after ASO treatment (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…hSOD1 was isolated from transgenic rat tissue or CSF as described previously 24. Before immunoprecipitation, 200 ng of N15‐labeled hSOD1 was added to each brain or spinal cord sample, and 50 ng of N15 SOD1 was added to CSF samples.…”

Section: Methodsmentioning

confidence: 99%

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Protein production is an early biomarker for RNA‐targeted therapies

Self

Schoch

Alex

et al. 2018

Ann Clin Transl Neurol

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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.

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“…The amount of 13 C 6 ‐Leucine found in plasma, the precursor for leucine found in the central nervous system,24 was consistent in all experiments between groups (Figure S1). …”

Section: Methodssupporting

confidence: 69%

Section: Discussionmentioning

confidence: 99%

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Protein production is an early biomarker for RNA‐targeted therapies

Self

Schoch

Alex

et al. 2018

Ann Clin Transl Neurol

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“…Stable isotope-labeling kinetics quantitation, for example, enables investigators to assess the kinetics of tau metabolism under physiological conditions, as tau is generated, post-translationally modified, spreads, and is degraded over the course of the disease [46].…”

Section: Biomarkers and Other Toolsmentioning

confidence: 99%

Tau: From research to clinical development

Holtzman

Carrillo

Hendrix

et al. 2016

Alzheimer's & Dementia

128

102

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Alzheimer's Association Research Roundtable Fall 2015-Tau: From research to clinical development. Tau pathology is recognized as the key driver of disease progression in Alzheimer's and other neurodegenerative diseases. Although this makes tau an attractive target for the development of novel diagnostic and therapeutic strategies, the mechanisms underlying the onset and progression of tau-related neurotoxicity remain elusive. Recent strides in the development of sophisticated preclinical models and the emergence of tau PET imaging and fluid biomarkers provide new opportunities to increase our understanding of tau biology, overcome translational challenges, and accelerate the advancement of tau therapeutics from bench to bedside. With this in mind, the Alzheimer's Association convened a Research Roundtable in October 2015, bringing together experts from academia, industry, and regulatory agencies to discuss the latest understanding of tau pathogenic pathways and review the evolution of tau therapeutics and biomarkers currently in development. The meeting provided a forum to share experience and expertise with the common goal of advancing the discovery and development of new treatment strategies and expediting the design and implementation of efficient clinical trials.

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“…3 The second most common cause of FALS is the gene encoding copper zinc superoxide dismutase 1 (SOD1), which accounts for 10-20% of FALS and mostly follow an autosomal-dominant inheritance pattern, 4 although an aspartic acid to alanine (D90A) point mutation found in the Scandanavian population displays recessive inheritance. 5 Multiple efforts (ClinicalTrials.gov NCT00706147) [6][7][8][9][10][11][12][13][14][15][16][17] have focused on targeted therapeutic approaches for SOD1-related ALS (ALS SOD1 ).…”

Section: Introductionmentioning

confidence: 99%

Defining SOD1 ALS natural history to guide therapeutic clinical trial design

Bali

Self

Liu

et al. 2016

J Neurol Neurosurg Psychiatry

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Importance Understanding the natural history of familial amyotrophic lateral sclerosis (ALS) caused by SOD1 mutations (ALSSOD1) will provide key information for optimising clinical trials in this patient population. Objective To establish an updated natural history of ALSSOD1. Design, setting and participants Retrospective cohort study from 15 medical centres in North America evaluated records from 175 patients with ALS with genetically confirmed SOD1 mutations, cared for after the year 2000. Main outcomes and measures Age of onset, survival, ALS Functional Rating Scale (ALS-FRS) scores and respiratory function were analysed. Patients with the A4V (Ala-Val) SOD1 mutation (SOD1A4V), the largest mutation population in North America with an aggressive disease progression, were distinguished from other SOD1 mutation patients (SOD1non-A4V) for analysis. Results Mean age of disease onset was 49.7 ±12.3 years (mean±SD) for all SOD1 patients, with no statistical significance between SOD1A4V and SOD1non-A4V (p=0.72, Kruskal-Wallis). Total SOD1 patient median survival was 2.7 years. Mean disease duration for all SOD1 was 4.6±6.0 and 1.4±0.7 years for SOD1A4V. SOD1A4V survival probability (median survival 1.2 years) was significantly decreased compared with SOD1non-A4V (median survival 6.8 years; p<0.0001, log-rank). A statistically significant increase in ALS-FRS decline in SOD1A4V compared with SOD1non-A4V participants (p=0.02) was observed, as well as a statistically significant increase in ALS-forced vital capacity decline in SOD1A4V compared with SOD1non-A4V (p=0.02). Conclusions and relevance SOD1A4V is an aggressive, but relatively homogeneous form of ALS. These SOD1-specific ALS natural history data will be important for the design and implementation of clinical trials in the ALSSOD1 patient population.

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In vivo kinetic approach reveals slow SOD1 turnover in the CNS

Cited by 55 publications

References 41 publications

Protein production is an early biomarker for RNA‐targeted therapies

Protein production is an early biomarker for RNA‐targeted therapies

Tau: From research to clinical development

Defining SOD1 ALS natural history to guide therapeutic clinical trial design

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