Home LiteratureArticle Details
PMID: 16878173 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Antisense oligonucleotide therapy for neurodegenerative disease.

The Journal of clinical investigation ·Vol. 116 ·No. 8 ·2006-08-00 ·Pages 2290-6

Smith RA, Miller TM, Yamanaka K, Monia BP, Condon TP, Hung G, Lobsiger CS, Ward CM, McAlonis-Downes M, Wei H, Wancewicz EV, Bennett CF, Cleveland DW

Abstract

Neurotoxicity from accumulation of misfolded/mutant proteins is thought to drive pathogenesis in neurodegenerative diseases. Since decreasing levels of proteins responsible for such accumulations is likely to ameliorate disease, a therapeutic strategy has been developed to downregulate almost any gene in the CNS. Modified antisense oligonucleotides, continuously infused intraventricularly, have been demonstrated to distribute widely throughout the CNS of rodents and primates, including the regions affected in the major neurodegenerative diseases. Using this route of administration, we found that antisense oligonucleotides to superoxide dismutase 1 (SOD1), one of the most abundant brain proteins, reduced both SOD1 protein and mRNA levels throughout the brain and spinal cord. Treatment initiated near onset significantly slowed disease progression in a model of amyotrophic lateral sclerosis (ALS) caused by a mutation in SOD1. This suggests that direct delivery of antisense oligonucleotides could be an effective, dosage-regulatable means of treating neurodegenerative diseases, including ALS, where appropriate target proteins are known.

MeSH Terms
Animals Base Sequence Fibroblasts/drug effects,enzymology Macaca mulatta Motor Neuron Disease/enzymology Neurodegenerative Diseases/drug therapy Oligonucleotides, Antisense/metabolism,pharmacology,therapeutic use Protein Folding RNA, Messenger/genetics Rats Superoxide Dismutase/genetics Superoxide Dismutase-1 Ventricular Function
Chemicals
Oligonucleotides, Antisense RNA, Messenger Sod1 protein, rat Superoxide Dismutase Superoxide Dismutase-1
Authors & Affiliations
13 authors, click to expand affiliations / ORCID
Smith Richard A
Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, California, USA.
Miller Timothy M
Yamanaka Koji
Monia Brett P
Condon Thomas P
Hung Gene
Lobsiger Christian S
Ward Chris M
McAlonis-Downes Melissa
Wei Hongbing
Wancewicz Ed V
Bennett C Frank
Cleveland Don W
References (52)
52 references, click to expand
  1. Strategies for the design and delivery of antisense oligonucleotides in central nervous system.
    Methods Enzymol. 2000;314:121-35 PMID: 10565009
  2. Virus-delivered small RNA silencing sustains strength in amyotrophic lateral sclerosis.
    Ann Neurol. 2005 May;57(5):773-6 PMID: 15852369
  3. Reduction of liver Fas expression by an antisense oligonucleotide protects mice from fulminant hepatitis.
    Nat Biotechnol. 2000 Aug;18(8):862-7 PMID: 10932156
  4. BACE1 is the major beta-secretase for generation of Abeta peptides by neurons.
    Nat Neurosci. 2001 Mar;4(3):233-4 PMID: 11224536
  5. Decreased nuclear beta-catenin, tau hyperphosphorylation and neurodegeneration in GSK-3beta conditional transgenic mice.
    EMBO J. 2001 Jan 15;20(1-2):27-39 PMID: 11226152
  6. Focal loss of the glutamate transporter EAAT2 in a transgenic rat model of SOD1 mutant-mediated amyotrophic lateral sclerosis (ALS).
    Proc Natl Acad Sci U S A. 2002 Feb 5;99(3):1604-9 PMID: 11818550
  7. Mutant SOD1 causes motor neuron disease independent of copper chaperone-mediated copper loading.
    Nat Neurosci. 2002 Apr;5(4):301-7 PMID: 11889469
  8. Toxic proteins in neurodegenerative disease.
    Science. 2002 Jun 14;296(5575):1991-5 PMID: 12065827
  9. siRNA-mediated gene silencing in vitro and in vivo.
    Nat Biotechnol. 2002 Oct;20(10):1006-10 PMID: 12244328
  10. Inhibition of glycogen synthase kinase-3 by lithium correlates with reduced tauopathy and degeneration in vivo.
    Proc Natl Acad Sci U S A. 2005 May 10;102(19):6990-5 PMID: 15867159
  11. Induction of toll-like receptors and NALP/PAN/PYPAF family members by modified oligonucleotides in lung epithelial carcinoma cells.
    Oligonucleotides. 2005 Summer;15(2):105-18 PMID: 15989425
  12. Targeting BACE1 with siRNAs ameliorates Alzheimer disease neuropathology in a transgenic model.
    Nat Neurosci. 2005 Oct;8(10):1343-9 PMID: 16136043
  13. Fatality in mice due to oversaturation of cellular microRNA/short hairpin RNA pathways.
    Nature. 2006 May 25;441(7092):537-41 PMID: 16724069
  14. GSK-3alpha regulates production of Alzheimer's disease amyloid-beta peptides.
    Nature. 2003 May 22;423(6938):435-9 PMID: 12761548
  15. Killing the messenger: short RNAs that silence gene expression.
    Nat Rev Mol Cell Biol. 2003 Jun;4(6):457-67 PMID: 12778125
  16. Solid phase synthesis of phosphorothioate oligonucleotides utilizing diethyldithiocarbonate disulfide (DDD) as an efficient sulfur transfer reagent.
    Nucleosides Nucleotides Nucleic Acids. 2003 Apr;22(4):461-8 PMID: 12885126
  17. Retrograde viral delivery of IGF-1 prolongs survival in a mouse ALS model.
    Science. 2003 Aug 8;301(5634):839-42 PMID: 12907804
  18. Wild-type nonneuronal cells extend survival of SOD1 mutant motor neurons in ALS mice.
    Science. 2003 Oct 3;302(5642):113-7 PMID: 14526083
  19. Progress in antisense technology.
    Annu Rev Med. 2004;55:61-95 PMID: 14746510
  20. siRNA relieves chronic neuropathic pain.
    Nucleic Acids Res. 2004;32(5):e49 PMID: 15026538
  21. VEGF delivery with retrogradely transported lentivector prolongs survival in a mouse ALS model.
    Nature. 2004 May 27;429(6990):413-7 PMID: 15164063
  22. Antisense strategies.
    Curr Mol Med. 2004 Aug;4(5):465-87 PMID: 15267220
  23. Molecular pathways to neurodegeneration.
    Nat Med. 2004 Jul;10 Suppl:S2-9 PMID: 15272266
  24. RNAi suppresses polyglutamine-induced neurodegeneration in a model of spinocerebellar ataxia.
    Nat Med. 2004 Aug;10(8):816-20 PMID: 15235598
  25. Purification of tau, a microtubule-associated protein that induces assembly of microtubules from purified tubulin.
    J Mol Biol. 1977 Oct 25;116(2):207-25 PMID: 599557
  26. Purification and tissue level of the beta-amyloid peptide precursor of rat brain.
    J Biol Chem. 1991 May 5;266(13):8464-9 PMID: 1673681
  27. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis.
    Nature. 1993 Mar 4;362(6415):59-62 PMID: 8446170
  28. Disposition of the 14C-labeled phosphorothioate oligonucleotide ISIS 2105 after intravenous administration to rats.
    J Pharmacol Exp Ther. 1993 Dec;267(3):1181-90 PMID: 8166890
  29. Altered microtubule organization in small-calibre axons of mice lacking tau protein.
    Nature. 1994 Jun 9;369(6480):488-91 PMID: 8202139
  30. Superoxide dismutase 1 with mutations linked to familial amyotrophic lateral sclerosis possesses significant activity.
    Proc Natl Acad Sci U S A. 1994 Aug 16;91(17):8292-6 PMID: 8058797
  31. The precursor protein of non-A beta component of Alzheimer's disease amyloid is a presynaptic protein of the central nervous system.
    Neuron. 1995 Feb;14(2):467-75 PMID: 7857654
  32. Superoxide dismutase is an abundant component in cell bodies, dendrites, and axons of motor neurons and in a subset of other neurons.
    Proc Natl Acad Sci U S A. 1995 Feb 14;92(4):954-8 PMID: 7862672
  33. beta-Amyloid precursor protein-deficient mice show reactive gliosis and decreased locomotor activity.
    Cell. 1995 May 19;81(4):525-31 PMID: 7758106
  34. Targeted disruption of the Huntington's disease gene results in embryonic lethality and behavioral and morphological changes in heterozygotes.
    Cell. 1995 Jun 2;81(5):811-23 PMID: 7774020
  35. Increased apoptosis and early embryonic lethality in mice nullizygous for the Huntington's disease gene homologue.
    Nat Genet. 1995 Oct;11(2):155-63 PMID: 7550343
  36. Motor neurons in Cu/Zn superoxide dismutase-deficient mice develop normally but exhibit enhanced cell death after axonal injury.
    Nat Genet. 1996 May;13(1):43-7 PMID: 8673102
  37. Endoproteolysis of presenilin 1 and accumulation of processed derivatives in vivo.
    Neuron. 1996 Jul;17(1):181-90 PMID: 8755489
  38. Quantitation of phosphorothioate oligonucleotides in human plasma.
    Anal Biochem. 1996 Mar 1;235(1):36-43 PMID: 8850544
  39. Epidemiology of mutations in superoxide dismutase in amyotrophic lateral sclerosis.
    Ann Neurol. 1997 Feb;41(2):210-21 PMID: 9029070
  40. Antisense oligonucleotide inhibitors for the treatment of cancer: 1. Pharmacokinetic properties of phosphorothioate oligodeoxynucleotides.
    Anticancer Drug Des. 1997 Jul;12(5):383-93 PMID: 9236854
  41. Cellular distribution of phosphorothioate oligodeoxynucleotides in normal rodent tissues.
    Lab Invest. 1997 Oct;77(4):379-88 PMID: 9354772
  42. Mutant genes in familial Alzheimer's disease and transgenic models.
    Annu Rev Neurosci. 1998;21:479-505 PMID: 9530504
  43. Aggregation and motor neuron toxicity of an ALS-linked SOD1 mutant independent from wild-type SOD1.
    Science. 1998 Sep 18;281(5384):1851-4 PMID: 9743498
  44. Characterization of a potent and specific class of antisense oligonucleotide inhibitor of human protein kinase C-alpha expression.
    J Biol Chem. 1999 Jan 15;274(3):1715-22 PMID: 9880552
  45. Therapeutic applications of implantable drug delivery systems.
    J Pharmacol Toxicol Methods. 1998 Jul;40(1):1-12 PMID: 9920528
  46. Development and validation of real-time quantitative reverse transcriptase-polymerase chain reaction for monitoring gene expression in cardiac myocytes in vitro.
    Anal Biochem. 1999 May 15;270(1):41-9 PMID: 10328763
  47. Sequence-dependent cytotoxicity of second-generation oligonucleotides.
    Nucleic Acids Res. 2004;32(22):6585-94 PMID: 15604456
  48. Lentiviral-mediated silencing of SOD1 through RNA interference retards disease onset and progression in a mouse model of ALS.
    Nat Med. 2005 Apr;11(4):423-8 PMID: 15768028
  49. Silencing mutant SOD1 using RNAi protects against neurodegeneration and extends survival in an ALS model.
    Nat Med. 2005 Apr;11(4):429-33 PMID: 15768029
  50. RNA interference improves motor and neuropathological abnormalities in a Huntington's disease mouse model.
    Proc Natl Acad Sci U S A. 2005 Apr 19;102(16):5820-5 PMID: 15811941
  51. Elevation of the Hsp70 chaperone does not effect toxicity in mouse models of familial amyotrophic lateral sclerosis.
    J Neurochem. 2005 May;93(4):875-82 PMID: 15857390
  52. RNAi: double-stranded RNA directs the ATP-dependent cleavage of mRNA at 21 to 23 nucleotide intervals.
    Cell. 2000 Mar 31;101(1):25-33 PMID: 10778853
Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI25424
Published
2006-08-00
Epub
2006-00-27
Pages
2290-6
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC1518790
Subset
IM
Grants
NINDS NIH HHS · R01 NS027036 · United States
NINDS NIH HHS · R37 NS027036 · United States
NINDS NIH HHS · NS27036 · United States
External Links
PubMed source DOI: 10.1172/JCI25424 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2