Skip to main content
SpringerLink
Log in

Molecular therapeutic strategies in hepatitis B virus infection

  • Review
  • Published:
The clinical investigator Aims and scope Submit manuscript

Abstract

Chronic infection with the hepatitis B virus is a major health problem worldwide. The only established therapy is interferon-α, with an efficacy of only 30–40% in highly selected patients. Nucleoside analogues do not show a significant clinical benefit. Molecular therapeutic strategies aimed at blocking gene expression include antisense DNA/RNA and ribozymes acting at the posttranscriptional level and triple helix formation blocking at the transcriptional level. In vitro, antisense oligodeoxynucleotides inhibit viral replication and gene expression in human hepatoma cell lines. In vivo, an antisense oligodeoxynucleotide directed against the 5′-region of the pre-S gene of the duck hepatitis B virus inhibited viral replication and gene expression in ducks. In vitro, ribozymes accurately cleave HBV substrate RNA. Triple helix formation is another very promising molecular approach. Results in hepadnaviral infection are not yet available, however.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

cccDNA:

covalently closed circular DNA

HBsAg:

hepatitis B surface antigen; HBV hepatitis B virus

References

  1. Agrawal S, Temsamani J, Tang JY (1991) Pharmacokinetics, biodistribution, and stability of oligodeoxynucleotide phosphorothioates in mice. Proc Natl Acad Sci USA 88:7595–7599

    CAS  PubMed  Google Scholar 

  2. Anderson WF (1992)Human gene therapy. Science 256:808–813

    Google Scholar 

  3. Azad RF, Driver VB, Tanaka K, Crooke RM, Anderson KP (1993) Antiviral activity of a phosphorothioate oligonucleotide complementary to RNA of the human cytomegalovirus major immediate-early region. Antimicrob Agents Chemother 37:1945–1954

    Google Scholar 

  4. Barrett JC, Miller PS, Ts'o POP (1974) Inhibitory effect of complex formation with oligodeoxynucleotide ethyl phosphotriesters on transfer ribonucleic acid aminoacylation. Biochemistry 13:4897–4906

    Google Scholar 

  5. Blum HE, Galun E, von Weizsäcker F, Wands JR (1991) Inhibition of hepatitis B virus by antisense oligodeoxynucleotides. Lancet 337:1230

    Google Scholar 

  6. Calabretta B (1991) Inhibition of protooncogene expression by antisense oligodeoxynucleotides: biological and therapeutic implications. Cancer Res 51:5404–5410

    Google Scholar 

  7. Cantin EM, Woolf TM (1993) Antisense oligonucleotides as antiviral agents: prospects and problems. Trends Microbiol 1:270–276

    Google Scholar 

  8. Cech TR, Zaug AJ, Grabowski PJ (1981) In vitro splicing of the ribosomal RNA precursor of Tetrahymena: involvement of a guanosine nucleotide in the excision of the intervening sequence. Cell 31:487–496

    Google Scholar 

  9. Cowsert LM, Fox MC, Zon G, Mirabelli CK (1993) In vitro evaluation of phosphorothioate oligonucleotides targeted to the E2 mRNA of papillomavirus: potential treatment of genital warts. Antimicrob Agents Chemother 37:171–177

    Google Scholar 

  10. Duval-Valentin G, Thuong NT, Helene C (1992) Specific inhibition of transcription by triple helix-forming oligonucleotides. Proc Natl Acad Sci USA 89:504–508

    Google Scholar 

  11. Green PJ, Pines O, Inouye M (1986) The role of antisense RNA in gene regulation. Annu Rev Biochem 55:569–597

    Google Scholar 

  12. Goodarzi G, Gross SC, Tewari A, Watabe A (1990) Antisense oligodeoxyribonucleotides inhibit the expression of the gene for hepatitis B virus surface antigen. J Gen Virol 71:3021–3025

    Google Scholar 

  13. Haseloff J, Gerlach WL (1988) Simple RNA enzymes with new and highly specific endoribonuclease activities. Nature 334:585–591

    Google Scholar 

  14. Helene C, Toulme J-J (1990) Specific regulation of gene expression by antisense, sense and antigene nucleic acids. Biochim Biophys Acta 1049:99–125

    Google Scholar 

  15. James W (1991) Towards gene-inhibition therapy: a review of progress and prospects in the field of antiviral antisense nucleic acids and ribozymes. Antiviral Chem Chemother 2:191–214

    Google Scholar 

  16. Kabanov AV, Vinogradov SV, Ovcharenko AV, Krivonos AV, Melik- Nubarov NS, Kiselev VI, Severin ES (1990) A new class of hydrophobic substituent effectively inhibit influenza virus production and synthesis of virus-specific proteins in MDCK cells. FEBS Lett 259:327–330

    Google Scholar 

  17. Korba B, Wells F, Jones K, Engle R, Buckler-White A, Gerin J (1994) Inhibition of hepatitis B virus replication in vitro by antisense oligonucleotides. Antiviral Res 23: [Suppl 1]: 78

    Google Scholar 

  18. Lau JYN, Wright TL (1993) Molecular virology and pathogenesis of hepatitis B. Lancet 343:1335–1344

    Google Scholar 

  19. Leonetti JP, Mechti N, Degols G, Gagnor C, Lebleu B (1991) Intracellular distribution of microinjected antisense oligonucleotides. Proc Natl Acad Sci USA 88:2702–2706

    Google Scholar 

  20. Marion PL, Oshiro LS, Regnery DC,Scullard GH, Robinson WS (1980) A virus in Beechey ground squirrels that is related to hepatitis B virus of humans. Proc Natl Acad Sci USA 77:2941–2944

    Google Scholar 

  21. Mason WS, Seal G, Summers J (1980) Virus of Pekin ducks with structural and biological relatedness to human hepatitis B virus. J Virol 36:829–836

    Google Scholar 

  22. Morgan RA, Anderson WF (1993) Human gene therapy. Annu Rev Biochem 62:191–217

    Google Scholar 

  23. Moser HE, Dervan PB (1987) Sequence-specific cleavage of double helical DNA by triple helix formation. Science 238:645–650

    Google Scholar 

  24. Offensperger W-B, Offensperger S, Walter E, Teubner K, Igloi G, Blum HE, Gerok W (1993) In vivo inhibition of duck hepatitis B virus replication and gene expression by phosphorothioate modified antisense oligodeoxynucleotides. EMBO J 12:1257–1262

    Google Scholar 

  25. Smith CC, Aurelian L, Reddy MP, Miller PS, Ts'o POP (1986) Antiviral effect of a oligo(nucleoside methylphosphonate) 16 complementary to the splice junction of herpes simplex virus type 1 immediate early pre-mRNAs 4 and 5. Proc Natl Acad Sci USA 83:2787–2791

    Google Scholar 

  26. Sprengel R, Kaleta EF, Will H (1988) Isolation and characterization of hepatitis B virus endemic in herons. J Virol 62:3832–3839

    Google Scholar 

  27. Stein CA, Cheng Y-C (1993) Antisense oligonucleotides as therapeutic agents — is the bullet really magical? Science 261:1004–1012

    Google Scholar 

  28. Stein CA, Cohen JS (1988) Oligodeoxynucleotides as inhibitors of gene expression. Cancer Res 48:2659–2668

    Google Scholar 

  29. Summers JW, Mason WS (1982) Replication of the genome of a hepatitis B-like virus by reverse transcription of an RNA intermediate. Cell 29:403–415

    Google Scholar 

  30. Summers J, Smolec JM, Snyder R (1978) A virus similar to hepatitis B virus associated with hepatitis and hepatoma in woodchucks. Proc Natl Acad Sci USA 75:4533–4537

    Google Scholar 

  31. Taniguchi T, Weissmann C (1978) Inhibition of Qβ RNA 70S ribosome initiation complex formation by an oligonucleotide complementary to the 3′ terminal region of E. coli 16S ribosomal RNA. Nature 275:770–772

    Google Scholar 

  32. Tiollais P, Pourcel C, Dejean A (1985) The hepatitis B virus. Nature 317:489–4953

    Google Scholar 

  33. Tuttleman JS, Pugh JC, Summers JW (1986) In vitro experimental infection of primary duck hepatocyte cultures with duck hepatitis B virus. J Virol 58:17–28

    Google Scholar 

  34. Wands JR, Blum HE (1991) Primary hepatocellular carcinoma. N Engl J Med 325:729–731

    Google Scholar 

  35. von Weizsacker F, Blum HE, Wands JR (1992) Cleavage of hepatitis B virus RNA by three ribozymes transcribed from a single DNA template. Biochem Biophys Res Commun 189:743–748

    Google Scholar 

  36. Wong DKH, Cheung AM, O'Rourke K, Naylor CD, Detsky AS, Heathcote J (1993) Effect of alpha-interferon treatment in patients with hepatitis B e antigen-positive chronic hepatitis B. Ann Intern Med 119:312–323

    Google Scholar 

  37. Wu GY, Wu CH (1992) Specific inhibition of hepatitis B viral gene expression in vitro by targeted antisense oligonucleotides. J Biol Chem267:12436–12439

    Google Scholar 

  38. Yao G-Q, Grill S, Egan W, Cheng Y-C (1993) Potent inhibition of Epstein-Barr virus by phosphorothioate oligodeoxynucleotides without sequence specification. Antimicrob Agents Chernother 37:1420–1425

    Google Scholar 

  39. Zamecnik PC, Stephenson ML (1978) Inhibition of Rous sarcoma virus replication and cell transformation by a specific oligodeoxynucleotide. Proc Natl Acad Sci USA 75:280–284

    Google Scholar 

  40. Zamecnik PC, Goodchild J, Taguchi Y, Sarin PS (1986) Inhibition of replication and expression of human T-cell lymphotropic virus type III in cultured cells by exogenous synthetic oligonucleotides complementary to viral RNA. Proc Natl Acad Sci USA 83:4143–4146

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Medizinische Universitatsklinik, Hugstetter Strasse 55, D-79106, Freiburg, Germany

    W. -B. Offensperger & W. Gerok

  2. Medizinische Universitatsklinik, Zurich, Switzerland

    H. E. Blum

Authors
  1. W. -B. Offensperger
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. H. E. Blum
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. W. Gerok
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

Correspondence to: W-B. Offensperger

Rights and permissions

Reprints and permissions

About this article

Cite this article

Offensperger, W.B., Blum, H.E. & Gerok, W. Molecular therapeutic strategies in hepatitis B virus infection. Clin Investig 72, 737–741 (1994). https://doi.org/10.1007/BF00180539

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00180539

Key words

Search

Navigation