Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

MicroRNA-mediated multi-tissue detargeting of oncolytic measles virus

Cancer Gene Therapy volume 21, pages 373–380 (2014)Cite this article

Subjects

Abstract

Precise oncotropism is required for successful systemic administration of next-generation oncolytic measles viruses (MVs). We have previously established a system for efficient post-entry targeting by insertion of synthetic microRNA target sites (miRTS) into the MV genome, thereby repressing replication in the presence of cognate microRNAs. Thus, differential expression of microRNAs, as frequently observed in normal compared with malignant tissues, can be exploited to increase vector specificity and safety. Here we report the combination of miRTS for different microRNAs in a single vector to detarget pivotal organs at risk during systemic administration (liver, brain, gastrointestinal tract). Accordingly, miRTS for miR-122, miR-7 and miR-148a that are enriched in these tissues were inserted to create multi-tissue-detargeted MV (MV-EGFPmtd). Replication of MV-EGFPmtd is repressed in cell lines as well as in non-transformed primary human hepatocytes and liver slices expressing cognate microRNAs. Oncolytic potency of MV-EGFPmtd is retained in a model of pancreatic cancer in vitro and in vivo. This work is a proof-of-concept that favorable expression profiles of multiple microRNAs can be exploited concomitantly to reshape the tropism of MV without compromising oncolytic efficacy. This strategy can be adapted to different vectors and cancer entities for safe and efficient high-dose systemic administration in clinical trials.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

References

  1. Galanis E, Hartmann L, Cliby W, Long H, Peethambaram P, Barrette B et al. Phase I trial of intraperitoneal administration of an oncolytic measles virus strain engineered to express carcinoembryonic antigen for recurrent ovarian cancer. Cancer Res 2010; 70: 875–882.

    Article  CAS  Google Scholar 

  2. Russell SJ, Federspiel MJ, Peng K, Tong C, Dingli D, Morice WG et al. Remission of disseminated cancer after systemic oncolytic virotherapy. Mayo Clin Proc 2014; 89 (7): 926–933.

    Article  Google Scholar 

  3. Esolen LM, Park SW, Hardwick JM, Griffin DE . Apoptosis as a cause of death in measles virus-infected cells. J Virol 1995; 69: 3955–3958.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Miest TS, Cattaneo R . New viruses for cancer therapy: meeting clinical needs. Nat Rev Microbiol 2014; 12: 23–34.

    Article  CAS  Google Scholar 

  5. Bossow S, Grossardt C, Temme A, Leber MF, Sawall S, Rieber EP et al. Armed and targeted measles virus for chemovirotherapy of pancreatic cancer. Cancer Gene Ther 2011; 18 (8): 598–608.

    Article  CAS  Google Scholar 

  6. Grossardt C, Engeland CE, Bossow S, Halama N, Zaoui K, Leber MF et al. Granulocyte-macrophage colony-stimulating factor-armed oncolytic measles virus is an effective therapeutic cancer vaccine. Hum Gene Ther 2013; 24: 644–654.

    Article  CAS  Google Scholar 

  7. Leber M, Bossow S, Leonard V, Zaoui K, Grossardt C, Frenzke M et al. MicroRNA-sensitive oncolytic measles viruses for cancer-specific vector tropism. Mol Ther 2011; 19: 1097–1106.

    Article  CAS  Google Scholar 

  8. Ungerechts G, Frenzke ME, Yaiw K, Miest T, Johnston PB, Cattaneo R . Mantle cell lymphoma salvage regimen: synergy between a reprogrammed oncolytic virus and two chemotherapeutics. Gene Therapy 2010; 17: 1506–1516.

    Article  CAS  Google Scholar 

  9. Miest T, Yaiw K, Frenzke M, Lampe J, Hudacek A, Springfeld C et al. Envelope-chimeric entry-targeted measles virus escapes neutralization and achieves oncolysis. Mol Ther 2011; 19: 1813–1820.

    Article  CAS  Google Scholar 

  10. Kaufmann JK, Bossow S, Grossardt C, Sawall S, Kupsch J, Erbs P et al. Chemovirotherapy of malignant melanoma with a targeted and armed oncolytic measles virus. J Invest Dermatol 2013; 133: 1034–1042.

    Article  CAS  Google Scholar 

  11. Navaratnarajah CK, Miest TS, Carfi A, Cattaneo R . Targeted entry of enveloped viruses: measles and herpes simplex virus I. Curr Opin Virol 2012; 2: 43–49.

    Article  CAS  Google Scholar 

  12. Ungerechts G, Springfeld C, Frenzke M, Lampe J, Johnston P, Parker W et al. Lymphoma chemovirotherapy: CD20-targeted and convertase-armed measles virus can synergize with fludarabine. Cancer Res 2007; 67: 10939–10947.

    Article  CAS  Google Scholar 

  13. Ungerechts G, Springfeld C, Frenzke M, Lampe J, Parker W, Sorscher E et al. An immunocompetent murine model for oncolysis with an armed and targeted measles virus. Mol Ther 2007; 15: 1991–1997.

    Article  CAS  Google Scholar 

  14. Friedrich K, Hanauer JR, Prufer S, Munch RC, Volker I, Filippis C et al. DARPin-targeting of measles virus: unique bispecificity, effective oncolysis, and enhanced safety. Mol Ther 2013; 21: 849–859.

    Article  CAS  Google Scholar 

  15. Hudacek AW, Navaratnarajah CK, Cattaneo R . Development of measles virus-based shielded oncolytic vectors: suitability of other paramyxovirus glycoproteins. Cancer Gene Ther 2013; 20: 109–116.

    Article  CAS  Google Scholar 

  16. Edge RE, Falls TJ, Brown CW, Lichty BD, Atkins H, Bell JC . A let-7 MicroRNA-sensitive vesicular stomatitis virus demonstrates tumor-specific replication. Mol Ther 2008; 16: 1437–1443.

    Article  CAS  Google Scholar 

  17. Kelly E, Hadac E, Greiner S, Russell S . Engineering microRNA responsiveness to decrease virus pathogenicity. Nat Med 2008; 14: 1278–1283.

    Article  CAS  Google Scholar 

  18. Kelly EJ, Nace R, Barber GN, Russell SJ . Attenuation of vesicular stomatitis virus encephalitis through microRNA targeting. J Virol 2010; 84: 1550–1562.

    Article  CAS  Google Scholar 

  19. Lee Cleo YF, Rennie PS, Jia WW . MicroRNA regulation of oncolytic herpes simplex virus-1 for selective killing of prostate cancer cells. Clin Cancer Res 2009; 15: 5126–5135.

    Article  CAS  Google Scholar 

  20. Ylosmaki E, Hakkarainen T, Hemminki A, Visakorpi T, Andino R, Saksela K . Generation of a conditionally replicating adenovirus based on targeted destruction of E1A mRNA by a cell type-specific MicroRNA. J Virol 2008; 82: 11009–11015.

    Article  CAS  Google Scholar 

  21. Myers RM, Greiner SM, Harvey ME, Griesmann G, Kuffel MJ, Buhrow SA et al. Preclinical pharmacology and toxicology of intravenous MV-NIS, an oncolytic measles virus administered with or without cyclophosphamide. Clin Pharmacol Ther 2007; 82: 700–710.

    Article  CAS  Google Scholar 

  22. Chang J, Nicolas E, Marks D, Sander C, Lerro A, Buendia M et al. miR-122, a mammalian liver-specific microRNA, is processed from hcr mRNA and may downregulate the high affinity cationic amino acid transporter CAT-1. RNA Biol 2004; 1: 106–113.

    Article  CAS  Google Scholar 

  23. Kutay H, Bai S, Datta J, Motiwala T, Pogribny I, Frankel W et al. Downregulation of miR-122 in the rodent and human hepatocellular carcinomas. J Cell Biochem 2006; 99: 671–678.

    Article  CAS  Google Scholar 

  24. Bai S, Nasser M, Wang B, Hsu S, Datta J, Kutay H et al. MicroRNA-122 inhibits tumorigenic properties of hepatocellular carcinoma cells and sensitizes these cells to sorafenib. J Biol Chem 2009; 284: 32015–32027.

    Article  CAS  Google Scholar 

  25. Fu X, Rivera A, Tao L, De G, Zhang X . Construction of an oncolytic herpes simplex virus that precisely targets hepatocellular carcinoma cells. Mol Ther 2011; 20 (2): 339–346.

    Article  Google Scholar 

  26. Ylosmaki E, Lavilla-Alonso S, Jaamaa S, Vaha-Koskela M, af Hallstrom T, Hemminki A et al. MicroRNA-mediated suppression of oncolytic adenovirus replication in human liver. PLoS One 2013; 8: e54506.

    Article  CAS  Google Scholar 

  27. Szafranska AE, Davison TS, John J, Cannon T, Sipos B, Maghnouj A et al. MicroRNA expression alterations are linked to tumorigenesis and non-neoplastic processes in pancreatic ductal adenocarcinoma. Oncogene 2007; 26: 4442–4452.

    Article  CAS  Google Scholar 

  28. Bloomston M, Frankel W, Petrocca F, Volinia S, Alder H, Hagan J et al. MicroRNA expression patterns to differentiate pancreatic adenocarcinoma from normal pancreas and chronic pancreatitis. JAMA 2007; 297: 1901–1908.

    Article  CAS  Google Scholar 

  29. Mestdagh P, Lefever S, Pattyn F, Ridzon D, Fredlund E, Fieuw A et al. The microRNA body map: dissecting microRNA function through integrative genomics. Nucleic Acids Res 2011; 39: e136.

    Article  CAS  Google Scholar 

  30. Radecke F, Spielhofer P, Schneider H, Kaelin K, Huber M, Dotsch C et al. Rescue of measles viruses from cloned DNA. EMBO J 1995; 14: 5773–5784.

    Article  CAS  Google Scholar 

  31. Muhlebach MD, Schaser T, Zimmermann M, Armeanu S, Hanschmann KO, Cattaneo R et al. Liver cancer protease activity profiles support therapeutic options with matrix metalloproteinase-activatable oncolytic measles virus. Cancer Res 2010; 70: 7620–7629.

    Article  Google Scholar 

  32. Zimmermann M, Weiland T, Bitzer M, Lauer UM . Preclinical testing of virotherapeutics for primary and secondary tumors of the liver. Methods Mol Biol 2012; 806: 121–136.

    Article  CAS  Google Scholar 

  33. Rima BK, Duprex WP . The measles virus replication cycle. Curr Top Microbiol Immunol 2009; 329: 77–102.

    CAS  PubMed  Google Scholar 

  34. Huntzinger E, Izaurralde E . Gene silencing by microRNAs: contributions of translational repression and mRNA decay. Nat Rev Genet 2011; 12: 99–110.

    Article  CAS  Google Scholar 

  35. Wild TF, Buckland R . Functional aspects of envelope-associated measles virus proteins. Curr Top Microbiol Immunol 1995; 191: 51–64.

    CAS  PubMed  Google Scholar 

  36. Wild TF, Malvoisin E, Buckland R . Measles virus: both the haemagglutinin and fusion glycoproteins are required for fusion. J Gen Virol 1991; 72 (Pt 2): 439–442.

    Article  CAS  Google Scholar 

  37. Russell SJ, Peng K, Bell JC . Oncolytic virotherapy. Nat Biotechnol 2012; 30: 658–670.

    Article  CAS  Google Scholar 

  38. Landgraf P, Rusu M, Sheridan R, Sewer A, Iovino N, Aravin A et al. A mammalian microRNA expression atlas based on small RNA library sequencing. Cell 2007; 129: 1401–1414.

    Article  CAS  Google Scholar 

  39. Hsu S, Chu C, Tsou A, Chen S, Chen H, Hsu PW et al. miRNAMap 2.0: genomic maps of microRNAs in metazoan genomes. Nucleic Acids Res 2008; 36: D165–D169.

    Article  CAS  Google Scholar 

  40. Sugio K, Sakurai F, Katayama K, Tashiro K, Matsui H, Kawabata K et al. Enhanced safety profiles of the telomerase-specific replication-competent adenovirus by incorporation of normal cell-specific microRNA-targeted sequences. Clin Cancer Res 2011; 17: 2807–2818.

    Article  CAS  Google Scholar 

  41. Negrini M, Gramantieri L, Sabbioni S, Croce CM . microRNA involvement in hepatocellular carcinoma. Anticancer Agents Med Chem 2011; 11: 500–521.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Silke Hamzaoui-Nord and Claudia Lay-Mees for their animal care support, Birgit Hoyler for technical support, Michael Mühlebach for the anti-F/-H antibodies, Roberto Cattaneo for his continuous support and the anti-N antibody, Jürgen Weitz and Hubertus Schmitz-Winnenthal for the primary liver material and Frank Bergmann for pathological analyses. This work was supported by Deutsche Krebshilfe (German Cancer Aid), Max Eder Program No. 110702 (to GU), DKFZ Heinrich F. C. Behr stipends (to MAB and MS) and a Helmholtz-Association/DKFZ PhD fellowship (to MFL). This work was done in Heidelberg, Germany.

Author information

Author notes

  1. M A Baertsch and M F Leber: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Translational Oncology, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany

    M A Baertsch, M F Leber, S Bossow, M Singh, C E Engeland, J Albert, C Grossardt, C von Kalle & G Ungerechts

  2. Department of Medical Oncology, National Center for Tumor Diseases (NCT) and Heidelberg University Hospital, Heidelberg, Germany

    D Jäger & G Ungerechts

Authors
  1. M A Baertsch
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M F Leber
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S Bossow
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. C E Engeland
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J Albert
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. C Grossardt
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. D Jäger
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. C von Kalle
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. G Ungerechts
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to G Ungerechts.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Baertsch, M., Leber, M., Bossow, S. et al. MicroRNA-mediated multi-tissue detargeting of oncolytic measles virus. Cancer Gene Ther 21, 373–380 (2014). https://doi.org/10.1038/cgt.2014.40

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/cgt.2014.40

This article is cited by

Search

Advanced search

Quick links