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Antimicrobial Agents and Chemotherapy, February 1999, p. 347-353, Vol. 43, No. 2
ISIS Pharmaceuticals, Inc., Carlsbad,
California 92008
Received 30 June 1998/Returned for modification 29 August
1998/Accepted 5 November 1998
Hepatitis C virus (HCV) is the major cause of non-A, non-B
hepatitis worldwide. Current treatments are not curative for most infected individuals, and there is an urgent need for both novel therapeutic agents and small-animal models which can be used to evaluate candidate drugs. A small-animal model of HCV gene expression was developed with recombinant vaccinia virus vectors. VHCV-IRES (internal ribosome entry site) is a recombinant vaccinia viral vector
containing the HCV 5' nontranslated region (5'-NTR) and a portion of
the HCV core coding region fused to the firefly luciferase gene.
Intraperitoneal injection of VHCV-IRES produced high levels of
luciferase activity in the livers of BALB/c mice. Antisense oligonucleotides complementary to the HCV 5'-NTR and translation initiation codon regions were then evaluated for their effects on the
expression of these target HCV sequences in BALB/c mice infected with
the vaccinia virus vector. Treatment of VHCV-IRES-infected mice with
20-base phosphorothioate oligonucleotides complementary to the sequence
surrounding the HCV initiation codon (nucleotides 330 to 349)
specifically reduced luciferase expression in the livers in a
dose-dependent manner. Inhibition of HCV reporter gene expression in
this small-animal model suggests that antisense oligonucleotides may
provide a novel therapy for treatment of chronic HCV infection.
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Antisense Oligonucleotide Inhibition of Hepatitis C
Virus (HCV) Gene Expression in Livers of Mice Infected with an
HCV-Vaccinia Virus Recombinant

and
*
Corresponding author. Mailing address: 2292 Faraday
Ave., Carlsbad, CA 92008. Phone: (760) 603-2322. Fax: (760) 603-3861. E-mail: kanderson{at}isisph.com.
Present address: Trega Biosciences, Inc., San Diego, CA 92121.
Present address: Invitrogen Corporation, Carlsbad, CA 92008.
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