SOD1 in Cerebral Spinal Fluid as a Pharmacodynamic Marker for Antisense Oligonucleotide Therapy

Winer, Leah; Srinivasan, Dushyanth; Chun, Seung; Lacomis, David; Jaffa, Matthew; Fagan, Anne M.; Holtzman, David M.; Wancewicz, Ed; Bennett, C. Frank; Bowser, Robert; Cudkowicz, Merit; Miller, Timothy M.

doi:10.1001/jamaneurol.2013.593

Cited by 97 publications

(89 citation statements)

References 30 publications

(35 reference statements)

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“…Previous work supports the use of CSF protein concentration as a promising pharmacodynamics biomarker for ASO therapy,26, 27 and CSF SOD1 concentration is a secondary outcome measurement in an ongoing Phase I clinical trial (NCT0262399). However, a key limitation in the use of CSF protein concentration as a measure of ASO efficacy is the indirect mechanism informed by this assay.…”

Section: Discussionmentioning

confidence: 86%

“…Additionally, both transgenic animal models used here express wild‐type forms of the target protein. 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.…”

Section: Discussionmentioning

confidence: 94%

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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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Section: Discussionmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 94%

Protein production is an early biomarker for RNA‐targeted therapies

Self

Schoch

Alex

et al. 2018

Ann Clin Transl Neurol

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“…For now, ASO technology targets all SOD1 mRNA, aiming to reduce levels of both wildtype and mutant SOD1, as the mutation is known to exert its effect through a toxic gain of function. In CSF, SOD1 protein levels have been shown to be higher in people with ALS than in healthy controls [50], but interindividual variability is high. Within an individual, SOD1 in the CSF is remarkably stable over time, and as such is an encouraging pharmacodynamic biomarker for SOD1-targeted ASO therapy.…”

Section: Toward Novel Outcome Measures and Biomarkers In Als Trialsmentioning

confidence: 99%

Clinical Trial Designs in Amyotrophic Lateral Sclerosis: Does One Design Fit All?

2015

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The last 2 decades have seen a surge in the number of amyotrophic lateral sclerosis (ALS) clinical trials with the hope of finding successful treatments. Clinical trialists aim to repurpose existing drugs and test novel compounds to target potential ALS disease pathophysiology. Recent technological advancements have led to the discovery of new causative genetic agents and modes of delivering potential therapy, calling for increasingly sophisticated trial design. The standard ALS clinical trial design may be modified depending on study needs: type of therapy; route of therapy delivery; phase of therapy development; applicable subpopulation; market availability of therapy; and utility of telemedicine. Novel biomarkers of diagnostic, predictive, prognostic, and pharmacodynamic value are undergoing development and validation for use in clinical trials. Design modifications build on the traditional clinical trial design and may be employed in either the learning or confirming trial phase. Novel designs aim to minimize patient risk, study duration, and sample size, while improving efficiency and promoting statistical power to herald an exciting era for clinical research in ALS.

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“…We originally targeted 15% based on our observations in our first study. However, subsequent studies showed that normal variation in CSF does not exceed 7.1% 10. Total CSF SOD1 content includes both wild‐type and mutant proteins.…”

Section: Discussionmentioning

confidence: 99%

Pyrimethamine significantly lowers cerebrospinal fluid Cu/Zn superoxide dismutase in amyotrophic lateral sclerosis patients with SOD1 mutations

Lange

Shahbazi

Silani

et al. 2017

Annals of Neurology

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ObjectiveCu/Zn superoxide dismutase (SOD1) reduction prolongs survival in SOD1‐transgenic animal models. Pyrimethamine produces dose‐dependent SOD1 reduction in cell culture systems. A previous phase 1 trial showed pyrimethamine lowers SOD1 levels in leukocytes in patients with SOD1 mutations. This study investigated whether pyrimethamine lowered SOD1 levels in the cerebrospinal fluid (CSF) in patients carrying SOD1 mutations linked to familial amyotrophic lateral sclerosis (fALS/SOD1).MethodsA multicenter (5 sites), open‐label, 9‐month‐duration, dose‐ranging study was undertaken to determine the safety and efficacy of pyrimethamine to lower SOD1 levels in the CSF in fALS/SOD1. All participants underwent 3 lumbar punctures, blood draw, clinical assessment of strength, motor function, quality of life, and adverse effect assessments. SOD1 levels were measured in erythrocytes and CSF. Pyrimethamine was measured in plasma and CSF. Appel ALS score, ALS Functional Rating Scale–Revised, and McGill Quality of Life Single‐Item Scale were measured at screening, visit 6, and visit 9.ResultsWe enrolled 32 patients; 24 completed 6 visits (18 weeks), and 21 completed all study visits. A linear mixed effects model showed a significant reduction in CSF SOD1 at visit 6 (p < 0.001) with a mean reduction of 13.5% (95% confidence interval [CI] = 8.4–18.5) and at visit 9 (p < 0.001) with a mean reduction of 10.5% (95% CI = 5.2–15.8).InterpretationPyrimethamine is safe and well tolerated in ALS. Pyrimethamine is capable of producing a significant reduction in total CSF SOD1 protein content in patients with ALS caused by different SOD1 mutations. Further long‐term studies are warranted to assess clinical efficacy. Ann Neurol 2017;81:837–848

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SOD1 in Cerebral Spinal Fluid as a Pharmacodynamic Marker for Antisense Oligonucleotide Therapy

Cited by 97 publications

References 30 publications

Protein production is an early biomarker for RNA‐targeted therapies

Protein production is an early biomarker for RNA‐targeted therapies

Clinical Trial Designs in Amyotrophic Lateral Sclerosis: Does One Design Fit All?

Pyrimethamine significantly lowers cerebrospinal fluid Cu/Zn superoxide dismutase in amyotrophic lateral sclerosis patients with SOD1 mutations

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