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Titolo:
Antisense-mediated down-regulation of the human huntingtin gene
Autore:
Boado, RJ; Kazantsev, A; Apostol, BL; Thompson, LM; Pardridge, WM;
Indirizzi:
Univ Calif Los Angeles, Sch Med, Dept Med, Los Angeles, CA 90095 USA Univ Calif Los Angeles Los Angeles CA USA 90095 Los Angeles, CA 90095 USA Univ Calif Los Angeles, Sch Med, Brain Res Inst, Los Angeles, CA 90095 USAUniv Calif Los Angeles Los Angeles CA USA 90095 Los Angeles, CA 90095 USA MIT, Ctr Canc Res, Dept Biol, Cambridge, MA 02139 USA MIT Cambridge MA USA 02139 r Canc Res, Dept Biol, Cambridge, MA 02139 USA Univ Calif Irvine, Coll Med, Dept Biol Chem, Irvine, CA 92717 USA Univ Calif Irvine Irvine CA USA 92717 ept Biol Chem, Irvine, CA 92717 USA
Titolo Testata:
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
fascicolo: 1, volume: 295, anno: 2000,
pagine: 239 - 243
SICI:
0022-3565(200010)295:1<239:ADOTHH>2.0.ZU;2-O
Fonte:
ISI
Lingua:
ENG
Soggetto:
BLOOD-BRAIN-BARRIER; GLUT1 GLUCOSE-TRANSPORTER; MESSENGER-RNA; DRUG-DELIVERY; IN-VIVO; PHOSPHOROTHIOATE OLIGODEOXYNUCLEOTIDE; MAMMALIAN-CELLS; DISEASE; OLIGONUCLEOTIDES; PHARMACOKINETICS;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
25
Recensione:
Indirizzi per estratti:
Indirizzo: Boado, RJ Univ Calif Los Angeles, Sch Med, Dept Med, Los Angeles, CA 90095USA Univ Calif Los Angeles Los Angeles CA USA 90095 s, CA 90095 USA
Citazione:
R.J. Boado et al., "Antisense-mediated down-regulation of the human huntingtin gene", J PHARM EXP, 295(1), 2000, pp. 239-243

Abstract

The present study determines whether the expression of the huntingtin genemight 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 [H-3] leucine into the huntingtin gene product in a dose-dependent manner (ED50 of similar to 11.5 mu M). 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 similar to 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 mu M) 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.

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Documento generato il 02/10/20 alle ore 01:42:49