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:

Liver transduction with a simian virus 40 vector encoding insulin-like growth factor I reduces hepatic damage and the development of liver cirrhosis

Gene Therapy volume 14, pages 203–210 (2007)Cite this article

Abstract

Liver transplantation is the only treatment for advanced liver cirrhosis. Therapies halting the progression of the disease are urgently needed. Administration of recombinant insulin-like growth factor-I (rIGF-I) induces hepatoprotective effects in experimental cirrhosis. Therefore, we analyzed the efficacy of a recombinant simian virus 40 vector (rSV40) encoding IGF-I (rSVIGF-I) to prevent cirrhosis progression. First, transgene expression was evaluated in mice injected with rSV40 encoding luciferase, which showed long-term hepatic expression of the transgene. Interestingly, luciferase expression increased significantly in CCl4-damaged livers and upon IGF-I administration, thus liver injury and IGF-I expression from rSVIGF-I should favor transgene expression. rSVIGF-I therapeutic efficacy was studied in rats where liver cirrhosis was induced by CCl4 inhalation during 36 weeks. At the end of the study, the hepatic levels of IGF-I and IGF-binding protein 3 were higher in rSVIGF-I-treated rats than in control cirrhotic animals. Cirrhotic rats treated with rSVIGF-I had reduced serum bilirubin, transaminases and liver fibrosis scores and increased hepatic expression of hepatocyte growth factor and STAT3α as compared to cirrhotic animals. Furthermore, cirrhotic animals showed testis atrophy and altered spermatogenesis, whereas testicular size and histology were normal in cirrhotic rats that received rSVIGF-I. Therefore, rSV40-mediated sustained expression of IGF-I in the liver slowed cirrhosis progression.

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

Similar content being viewed by others

References

  1. Bataller R, Brenner DA . Liver fibrosis. J Clin Invest 2005; 115: 209–218.

    Article  CAS  Google Scholar 

  2. Friedman SL . Molecular regulation of hepatic fibrosis, an integrated cellular response to tissue injury. J Biol Chem 2000; 275: 2247–2250.

    Article  CAS  Google Scholar 

  3. Friedman SL . Liver fibrosis – from bench to bedside. J Hepatol 2003; 38: S38–S53.

    Article  Google Scholar 

  4. De Palo EF, Bassanello M, Lancerin F, Spinella P, Gatti R, D'Amico D et al. GH/IGF system, cirrhosis and liver transplantation. Clin Chim Acta 2001; 310: 31–37.

    Article  CAS  Google Scholar 

  5. Adamo M, Lowe Jr WL, LeRoith D, Roberts CT . Insulin-like growth factor I messenger ribonucleic acids with alternative 5′-untranslated regions are differentially expressed during development of the rat. Endocrinology 1989; 124: 2737–2744.

    Article  CAS  Google Scholar 

  6. Yakar S, Liu JL, Stannard B, Butler A, Accili D, Sauer B et al. Normal growth and development in the absence of hepatic insulin-like growth factor I. Proc Natl Acad Sci USA 1999; 96: 7324–7329.

    Article  CAS  Google Scholar 

  7. Mohan S, Baylink DJ . IGF-binding proteins are multifunctional and act via IGF-dependent and -independent mechanisms. J Endocrinol 2002; 175: 19–31.

    Article  CAS  Google Scholar 

  8. Rajaram S, Baylink DJ, Mohan S . Insulin-like growth factor-binding proteins in serum and other biological fluids: regulation and functions. Endocr Rev 1997; 18: 801–831.

    CAS  Google Scholar 

  9. Castilla-Cortazar I, Garcia M, Quiroga J, Diez N, Diez-Caballero F, Calvo A et al. Insulin-like growth factor-I reverts testicular atrophy in rats with advanced cirrhosis. Hepatology 2000; 31: 592–600.

    Article  CAS  Google Scholar 

  10. Castilla-Cortazar I, Garcia M, Muguerza B, Quiroga J, Perez R, Santidrian S et al. Hepatoprotective effects of insulin-like growth factor I in rats with carbon tetrachloride-induced cirrhosis. Gastroenterology 1997; 113: 1682–1691.

    Article  CAS  Google Scholar 

  11. Muguerza B, Castilla-Cortazar I, Garcia M, Quiroga J, Santidrian S, Prieto J . Antifibrogenic effect in vivo of low doses of insulin-like growth factor-I in cirrhotic rats. Biochim Biophys Acta 2001; 1536: 185–195.

    Article  CAS  Google Scholar 

  12. Conchillo M, de Knegt RJ, Payeras M, Quiroga J, Sangro B, Herrero JI et al. Insulin-like growth factor I (IGF-I) replacement therapy increases albumin concentration in liver cirrhosis: results of a pilot randomized controlled clinical trial. J Hepatol 2005; 43: 630–636.

    Article  CAS  Google Scholar 

  13. Arad U, Zeira E, El-Latif MA, Mukherjee S, Mitchell L, Pappo O et al. Liver-targeted gene therapy by SV40-based vectors using the hydrodynamic injection method. Hum Gene Ther 2005; 16: 361–371.

    Article  CAS  Google Scholar 

  14. Strayer D, Branco F, Zern MA, Yam P, Calarota SA, Nichols CN et al. Durability of transgene expression and vector integration: recombinant SV40-derived gene therapy vectors. Mol Ther 2002; 6: 227–237.

    Article  CAS  Google Scholar 

  15. Vera M, Fortes P . Simian virus-40 as a gene therapy vector. DNA Cell Biol 2004; 23: 271–282.

    Article  CAS  Google Scholar 

  16. Duan YY, Wu J, Zhu JL, Liu SL, Ozaki I, Strayer DS et al. Gene therapy for human alpha1-antitrypsin deficiency in an animal model using SV40-derived vectors. Gastroenterology 2004; 127: 1222–1232.

    Article  CAS  Google Scholar 

  17. Sauter BV, Parashar B, Chowdhury NR, Kadakol A, Ilan Y, Singh H et al. A replication-deficient rSV40 mediates liver-directed gene transfer and a long-term amelioration of jaundice in gunn rats. Gastroenterology 2000; 119: 1348–1357.

    Article  CAS  Google Scholar 

  18. Sanz S, Pucilowska JB, Liu S, Rodriguez-Ortigosa CM, Lund PK, Brenner DA et al. Expression of insulin-like growth factor I by activated hepatic stellate cells reduces fibrogenesis and enhances regeneration after liver injury. Gut 2005; 54: 134–141.

    Article  CAS  Google Scholar 

  19. Poli G . Pathogenesis of liver fibrosis: role of oxidative stress. Mol Aspects Med 2000; 21: 49–98.

    Article  CAS  Google Scholar 

  20. Matsuda Y, Matsumoto K, Yamada A, Ichida T, Asakura H, Komoriya Y et al. Preventive and therapeutic effects in rats of hepatocyte growth factor infusion on liver fibrosis/cirrhosis. Hepatology 1997; 26: 81–89.

    Article  CAS  Google Scholar 

  21. Jacoby JJ, Kalinowski A, Liu MG, Zhang SS, Gao Q, Chai GX et al. Cardiomyocyte-restricted knockout of STAT3 results in higher sensitivity to inflammation, cardiac fibrosis, and heart failure with advanced age. Proc Natl Acad Sci USA 2003; 100: 12929–12934.

    Article  CAS  Google Scholar 

  22. Larrea E,, Aldabe R, Molano E, Fernandez-Rodriguez CM, Ametzazurra A, Civeira MP et al. Altered expression and activation of STATs (signal transduction and activator of transcription) in HCV infection: in vivo and in vitro studies. Gut (in press).

  23. Matsuno Y, Iwata H, Umeda Y, Takagi H, Mori Y, Kosugi A et al. Hepatocyte growth factor gene transfer into the liver via the portal vein using electroporation attenuates rat liver cirrhosis. Gene Therapy 2003; 10: 1559–1566.

    Article  CAS  Google Scholar 

  24. Ueki T, Kaneda Y, Tsutsui H, Nakanishi K, Sawa Y, Morishita R et al. Hepatocyte growth factor gene therapy of liver cirrhosis in rats. Nat Med 1999; 5: 226–230.

    Article  CAS  Google Scholar 

  25. Morales-Ruiz M, Cejudo-Martin P, Fernandez-Varo G, Tugues S, Ros J, Angeli P et al. Transduction of the liver with activated Akt normalizes portal pressure in cirrhotic rats. Gastroenterology 2003; 125: 522–531.

    Article  CAS  Google Scholar 

  26. Qi Z, Atsuchi N, Ooshima A, Takeshita A, Ueno H . Blockade of type beta transforming growth factor signaling prevents liver fibrosis and dysfunction in the rat. Proc Natl Acad Sci USA 1999; 96: 2345–2349.

    Article  CAS  Google Scholar 

  27. Ariosto F, Riggio O, Cantafora A, Colucci S, Gaudio E, Mechelli C et al. Carbon tetrachloride-induced experimental cirrhosis in the rat: a reappraisal of the model. Eur Surg Res 1989; 21: 280–286.

    Article  CAS  Google Scholar 

  28. Wong FW, Chan WY, Lee SS . Resistance to carbon tetrachloride-induced hepatotoxicity in mice which lack CYP2E1 expression. Toxicol Appl Pharmacol 1998; 153: 109–118.

    Article  CAS  Google Scholar 

  29. Chen GF, Ronis MJ, Ingelman-Sundberg M, Badger TM . Hormonal regulation of microsomal cytochrome P4502E1 and P450 reductase in rat liver and kidney. Xenobiotica 1999; 29: 437–451.

    Article  CAS  Google Scholar 

  30. Chan JM, Stampfer MJ, Ma J, Gann P, Gaziano JM, Pollak M et al. Insulin-like growth factor-I (IGF-I) and IGF binding protein-3 as predictors of advanced-stage prostate cancer. J Natl Cancer Inst 2002; 94: 1099–1106.

    Article  CAS  Google Scholar 

  31. Wu Y, Yakar S, Zhao L, Hennighausen L, LeRoith D . Circulating insulin-like growth factor-I levels regulate colon cancer growth and metastasis. Cancer Res 2002; 62: 1030–1035.

    CAS  PubMed  Google Scholar 

  32. Zaitoun AM, Apelqvist G, Wikell C, Al-Mardini H, Bengtsson F, Record CO . Quantitative studies of testicular atrophy following portacaval shunt in rats. Hepatology 1998; 28: 1461–1466.

    Article  CAS  Google Scholar 

  33. Vera M, Razquin N, Prieto J, Melero I, Fortes P, Gonzalez-Aseguinolaza G . Intratumoral injection of dendritic cells transduced by an SV40-based vector expressing interleukin-15 induces curative immunity mediated by CD8(+) T lymphocytes and NK cells. Mol Ther 2005; 12: 950–959.

    Article  CAS  Google Scholar 

  34. Vera M, Prieto J, Strayer DS, Fortes P . Factors influencing the production of recombinant SV40 vectors. Mol Ther 2004; 10: 780–791.

    Article  CAS  Google Scholar 

  35. Bustos M, Beraza N, Lasarte JJ, Baixeras E, Alzuguren P, Bordet T et al. Protection against liver damage by cardiotrophin-1: a hepatocyte survival factor up-regulated in the regenerating liver in rats. Gastroenterology 2003; 125: 192–201.

    Article  CAS  Google Scholar 

  36. Mirpuri E, Garcia-Trevijano ER, Castilla-Cortazar I, Berasain C, Quiroga J, Rodriguez-Ortigosa C et al. Altered liver gene expression in CCl4-cirrhotic rats is partially normalized by insulin-like growth factor-I. Int J Biochem Cell Biol 2002; 34: 242–252.

    Article  CAS  Google Scholar 

  37. Massoud TF, Gambhir SS . Molecular imaging in living subjects: seeing fundamental biological processes in a new light. Genes Dev 2003; 17: 545–580.

    Article  CAS  Google Scholar 

  38. Priego T, Granado M, Ibanez de Caceres I, Martin AI, Villanua MA, Lopez-Calderon A . Endotoxin at low doses stimulates pituitary GH whereas it decreases IGF-I and IGF-binding protein-3 in rats. J Endocrinol 2003; 179: 107–117.

    Article  CAS  Google Scholar 

  39. Chomczynski P, Sacchi N . Single-step method of RNA isolation by acid guanidinium thiocyanate–phenol–chloroform extraction. Anal Biochem 1987; 162: 156–159.

    Article  CAS  Google Scholar 

  40. Woessner Jr JF . The determination of hydroxyproline in tissue and protein samples containing small proportions of this imino acid. Arch Biochem Biophys 1961; 93: 440–447.

    Article  CAS  Google Scholar 

  41. Querejeta R, Varo N, Lopez B, Larman M, Artinano E, Etayo JC et al. Serum carboxy-terminal propeptide of procollagen type I is a marker of myocardial fibrosis in hypertensive heart disease. Circulation 2000; 101: 1729–1735.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank J Novo for providing rat IGF-I cDNA. Technical assistance by N Razquin and E Casales is thankfully acknowledged. M Wodecki help was essential in rat surgery. We also thank members of the lab for advice and Cristian Smedou and Ruben Hernandez for critical reading of the paper. This work was supported by CICYT (PM1999/0091), CICYT (SAF2003-01804), CICYT (SAF 2002-0327), FIS (01/1310 and 01/0843), Instituto Carlos III (C03/02 and PI051098), Education and Health Department of Navarra Government and through the ‘UTE project CIMA’. MV is an FPI fellow.

Author information

Author notes

  1. M Vera

    Present address: Mount Sinai School of Medicine, 1425 Madison Avenue, New York, 10029, NY, USA

  2. M Zaratiegui

    Present address: Cold Spring Harbor Laboratory, Bungtown Rd, Cold Spring Harbor, NY, 11724, USA

Authors and Affiliations

  1. Department of Hepatology and Gene Therapy, Center for Applied Medical Research (CIMA) and Clinica Universitaria, School of Medicine, University of Navarra, Pamplona, Spain

    M Vera, L Sobrevals, M Zaratiegui, L Martinez, B Palencia, C M Rodríguez, J Prieto & P Fortes

Authors
  1. M Vera
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. L Sobrevals
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M Zaratiegui
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. L Martinez
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. B Palencia
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. C M Rodríguez
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. J Prieto
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. P Fortes
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to P Fortes.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Vera, M., Sobrevals, L., Zaratiegui, M. et al. Liver transduction with a simian virus 40 vector encoding insulin-like growth factor I reduces hepatic damage and the development of liver cirrhosis. Gene Ther 14, 203–210 (2007). https://doi.org/10.1038/sj.gt.3302858

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gt.3302858

Keywords

This article is cited by

Search

Advanced search

Quick links