Document Detail


SOD1 in cerebral spinal fluid as a pharmacodynamic marker for antisense oligonucleotide therapy.
MedLine Citation:
PMID:  23147550     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: Therapies designed to decrease the level of SOD1 are currently in a clinical trial for patients with superoxide dismutase (SOD1)-linked familial amyotrophic lateral sclerosis (ALS).
OBJECTIVE: To determine whether the SOD1 protein in cerebral spinal fluid (CSF) may be a pharmacodynamic marker for antisense oligonucleotide therapy and a disease marker for ALS.
DESIGN: Antisense oligonucleotides targeting human SOD1 were administered to rats expressing SOD1G93A. The human SOD1 protein levels were measured in the rats' brain and CSF samples. In human CSF samples, the following proteins were measured: SOD1, tau, phosphorylated tau, VILIP-1, and YKL-40.
PARTICIPANTS: Ninety-three participants with ALS, 88 healthy controls, and 89 controls with a neurological disease (55 with dementia of the Alzheimer type, 19 with multiple sclerosis, and 15 with peripheral neuropathy).
RESULTS: Antisense oligonucleotide-treated SOD1G93A rats had decreased human SOD1 messenger RNA levels (mean [SD] decrease of 69% [4%]) and decreased protein levels (mean [SD] decrease of 48% [14%]) in the brain. The rats' CSF samples showed a similar decrease in hSOD1 levels (mean [SD] decrease of 42% [14%]). In human CSF samples, the SOD1 levels varied a mean (SD) 7.1% (5.7%) after additional measurements, separated by months, were performed. The CSF SOD1 levels were higher in the participants with ALS (mean [SE] level, 172 [8] ng/mL; P<.05) and the controls with a neurological disease (mean [SE] level, 172 [6] ng/mL; P<.05) than in the healthy controls (mean [SE] level, 134 [4] ng/mL). Elevated CSF SOD1 levels did not correlate with disease characteristics in participants with ALS or controls with dementia of the Alzheimer type, but they did correlate with tau, phosphorylated tau, VILIP-1 and YKL-40 levels in controls with dementia of the Alzheimer type.
CONCLUSIONS: SOD1 in CSF may be an excellent pharmacodynamic marker for SOD1-lowering therapies because antisense oligonucleotide therapy lowers protein levels in the rat brain and rat CSF samples and because SOD1 levels in CSF samples from humans are stable over time.
Authors:
Leah Winer; Dushyanth Srinivasan; Seung Chun; David Lacomis; Matthew Jaffa; Anne Fagan; David M Holtzman; Ed Wancewicz; C Frank Bennett; Robert Bowser; Merit Cudkowicz; Timothy M Miller
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  JAMA neurology     Volume:  70     ISSN:  2168-6157     ISO Abbreviation:  JAMA Neurol     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-02-20     Completed Date:  2013-04-16     Revised Date:  2014-02-04    
Medline Journal Info:
Nlm Unique ID:  101589536     Medline TA:  JAMA Neurol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  201-7     Citation Subset:  AIM; IM    
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MeSH Terms
Descriptor/Qualifier:
Aged
Amyotrophic Lateral Sclerosis / cerebrospinal fluid,  enzymology,  therapy
Animals
Biological Markers / cerebrospinal fluid
Brain / drug effects*,  enzymology*
Drug Delivery Systems / methods
Female
Humans
Male
Middle Aged
Oligonucleotides, Antisense / administration & dosage*,  therapeutic use
Rats
Superoxide Dismutase / antagonists & inhibitors,  cerebrospinal fluid*,  diagnostic use
Grant Support
ID/Acronym/Agency:
K08NS074194/NS/NINDS NIH HHS; P01 AG003991/AG/NIA NIH HHS; P01 AG026276/AG/NIA NIH HHS; P01-AG03991/AG/NIA NIH HHS; P01-AG26276/AG/NIA NIH HHS; P30 NS057105/NS/NINDS NIH HHS; P30-NS057105/NS/NINDS NIH HHS; P50 AG005681/AG/NIA NIH HHS; P50-AG05681/AG/NIA NIH HHS; R01 NS061867/NS/NINDS NIH HHS; R01 NS061867-01/NS/NINDS NIH HHS; RC1 NS068179/NS/NINDS NIH HHS; RC1 NS068179-01/NS/NINDS NIH HHS; UL1 RR024992/RR/NCRR NIH HHS; UL1 RR024992/RR/NCRR NIH HHS
Chemical
Reg. No./Substance:
0/Biological Markers; 0/Oligonucleotides, Antisense; EC 1.15.1.-/SOD1 G93A protein; EC 1.15.1.-/superoxide dismutase 1; EC 1.15.1.1/Superoxide Dismutase
Comments/Corrections

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