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Antimicrobial Agents and Chemotherapy, February 1999, p. 347-353, Vol. 43, No. 2
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

Hong Zhang, Ronnie Hanecak,dagger Vickie Brown-Driver, Raana Azad, Boyd Conklin, Maureen C. Fox,Dagger and Kevin P. Anderson*

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.

* Corresponding author. Mailing address: 2292 Faraday Ave., Carlsbad, CA 92008. Phone: (760) 603-2322. Fax: (760) 603-3861. E-mail: kanderson{at}isisph.com.

dagger Present address: Trega Biosciences, Inc., San Diego, CA 92121.

Dagger Present address: Invitrogen Corporation, Carlsbad, CA 92008.

Antimicrobial Agents and Chemotherapy, February 1999, p. 347-353, Vol. 43, No. 2
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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