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Research ArticleNEUROPHARMACOLOGY

Antisense-Mediated Down-Regulation of the Human Huntingtin Gene

Ruben J. Boado, Aleksey Kazantsev, Barbara L. Apostol, Leslie M. Thompson and William M. Pardridge
Journal of Pharmacology and Experimental Therapeutics October 2000, 295 (1) 239-243;
Ruben J. Boado
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Aleksey Kazantsev
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Barbara L. Apostol
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Leslie M. Thompson
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William M. Pardridge
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Abstract

The present study determines whether the expression of the huntingtin gene might be subject to antisense (AS)-mediated down-regulation. A series of AS oligodeoxynucleotides (ODNs) complementary to the huntingtin transcript [i.e., nucleotide (nt) −25 to 35] were designed and synthesized, and the AS efficacy was investigated by using a combination of in vitro transcription and translation to mimic in vivo conditions. An oligomer directed to nt −1 to 15 (ODN III) markedly reduced the incorporation of [3H]leucine into the huntingtin gene product in a dose-dependent manner (ED50 of ∼11.5 μM). ODNs that overlap with ODN III on both 5′- and 3′-flanking regions also produced translation arrest of the huntingtin protein; however, the AS-mediated effect of these ODNs represented ∼50% of the effect of ODN III. In contrast, an ODN directed to nt 19 to 35 had no AS effect. The efficacy of ODN III also was investigated in an inducible, stably transfected PC-12 cell line expressing a truncated huntingtin exon 1 protein. In accordance with the cell free translation studies, ODN III (1–10 μM) markedly decreased the abundance of the huntingtin-green fluorescence fusion protein to 40 to 46% of the control levels. In summary, a series of putative AS candidates were screened for down-regulation of the huntingtin gene, and an ODN molecule directed to the methionine initiation codon was identified with maximum AS effects.

Footnotes

  • Send reprint requests to: Dr. Ruben J. Boado, Department of Medicine, UCLA School of Medicine, Los Angeles, CA 90095. E-mail:rboado{at}mednet.ucla.edu

  • ↵1 This study was supported by the Hereditary Disease Foundation (Los Angeles, CA).

  • Abbreviations:
    HD
    Huntington's disease
    AS
    antisense
    ODN
    oligodeoxynucleotide
    PA
    ponasterone
    GFP
    green fluorescence protein
    NGF-β
    nerve growth factor-β
    PO
    phosphodiester
    nt
    nucleotide
    BBB
    blood-brain barrier
    PS
    phosphorothioate
    SA
    streptavidin
    PNA
    peptide nucleic acid
    • Received May 4, 2000.
    • Accepted June 19, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 295 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 295, Issue 1
1 Oct 2000
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Research ArticleNEUROPHARMACOLOGY

Antisense-Mediated Down-Regulation of the Human Huntingtin Gene

Ruben J. Boado, Aleksey Kazantsev, Barbara L. Apostol, Leslie M. Thompson and William M. Pardridge
Journal of Pharmacology and Experimental Therapeutics October 1, 2000, 295 (1) 239-243;

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Research ArticleNEUROPHARMACOLOGY

Antisense-Mediated Down-Regulation of the Human Huntingtin Gene

Ruben J. Boado, Aleksey Kazantsev, Barbara L. Apostol, Leslie M. Thompson and William M. Pardridge
Journal of Pharmacology and Experimental Therapeutics October 1, 2000, 295 (1) 239-243;
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