Therapy of hepadnavirus infection using antisense oligonucleotides

Chronic infection with the hepatitis B virus (HBV) is a major health problem worldwide. The only established therapy is alpha-interferon with an efficacy of only 30-40% in highly selected patients. Major theoretical problems of therapeutical strategies against hepadnaviral infections are the limited immune response and the presence of covalently closed HBV DNA in the nucleus. Many nucleoside analogues and inhibitors of viral reverse transcriptases were tested in vitro and in vivo with transient effects and often severe side effects. Molecular therapeutic strategies include antisense DNA/RNA and ribozymes. In vitro antisense oligodeoxynucleotides could be shown to inhibit viral replication and gene expression in human hepatoma cell lines. In vivo an antisense oligodeoxynucleotide directed against the 5'-region of the preS gene of the duck hepatitis B virus inhibited the viral replication and gene expression in ducks. These results demonstrate the potential clinical use of antisense DNA/RNA as antiviral therapeutics.