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Prolonged regulatable expression of EPO from an HSV vector using the LAP2 promoter element

Gene Therapy volume 19, pages 1107–1113 (2012)Cite this article

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Abstract

We previously reported regulated expression of erythropoietin (EPO) over 4 weeks in the peripheral nerve in vivo, using a herpes simplex virus (HSV)-based vector containing a Tet-on regulatable gene expression cassette. To create a vector that would be appropriate for the treatment of chronic neuropathy, we constructed a HSV vector with expression of EPO under the control of the Tet-on system in which the HSV latency-associated promoter 2 element was used to drive the expression of the Tet-on transactivator. EPO expression from the vector was tightly controlled by administration of doxycycline (DOX) in vitro. One month after inoculation of the vector to transduce dorsal root ganglion (DRG) in vivo, administration of DOX-containing chow-induced expression of EPO. Mice with streptozotocin-induced diabetes, inoculated with the vector, were protected against the development of neuropathy by continuous administration of DOX-containing chow over the course of 3 months. Identical results were achieved when DOX was administered every other week over 3 months of diabetes, but administration of DOX, 1 week out of 3, provided only partial protection against the development of neuropathy. Taken together, these results suggest such a vector is well suited for clinical trial for the treatment of chronic or subacutely developing neuropathy.

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References

  1. Hayakawa K, Itoh T, Niwa H, Mutoh T, Sobue G . NGF prevention of neurotoxicity induced by cisplatin, vincristine and taxol depends on toxicity of each drug and NGF treatment schedule: in vitro study of adult rat sympathetic ganglion explants. Brain Res 1998; 794: 313–319.

    Article  CAS  PubMed  Google Scholar 

  2. Hayakawa K, Sobue G, Itoh T, Mitsuma T . Nerve growth factor prevents neurotoxic effects of cisplatin, vincristine and taxol, on adult rat sympathetic ganglion explants in vitro. Life Sci 1994; 55: 519–525.

    Article  CAS  PubMed  Google Scholar 

  3. Kawashiri T, Egashira N, Itoh Y, Shimazoe T, Ikegami Y, Yano T et al. Neurotropin reverses paclitaxel-induced neuropathy without affecting anti-tumour efficacy. Eur J Cancer 2009; 45: 154–163.

    Article  CAS  PubMed  Google Scholar 

  4. Keswani SC, Leitz GJ, Hoke A . Erythropoietin is neuroprotective in models of HIV sensory neuropathy. Neurosci Lett 2004; 371: 102–105.

    Article  CAS  PubMed  Google Scholar 

  5. Bianchi R, Gilardini A, Rodriguez-Menendez V, Oggioni N, Canta A, Colombo T et al. Cisplatin-induced peripheral neuropathy: neuroprotection by erythropoietin without affecting tumour growth. Eur J Cancer 2007; 43: 710–717.

    Article  CAS  PubMed  Google Scholar 

  6. Apfel SC . Neurotrophic factor therapy--prospects and problems. Clin Chem Lab Med 2001; 39: 351–355.

    Article  CAS  PubMed  Google Scholar 

  7. Apfel SC . Is the therapeutic application of neurotrophic factors dead? Ann Neurol 2002; 51: 8–11.

    Article  PubMed  Google Scholar 

  8. Thoenen H, Sendtner M . Neurotrophins: from enthusiastic expectations through sobering experiences to rational therapeutic approaches. Nat Neurosci 2002; 5 (Suppl): 1046–1050.

    Article  CAS  PubMed  Google Scholar 

  9. Poduslo JF, Curran GL . Permeability at the blood-brain and blood-nerve barriers of the neurotrophic factors: NGF, CNTF, NT-3, BDNF. Brain Res Mol Brain Res 1996; 36: 280–286.

    Article  CAS  PubMed  Google Scholar 

  10. Petty BG, Cornblath DR, Adornato BT, Chaudhry V, Flexner C, Wachsman M et al. The effect of systemically administered recombinant human nerve growth factor in healthy human subjects. Ann Neurol 1994; 36: 244–246.

    Article  CAS  PubMed  Google Scholar 

  11. Chattopadhyay M, Wolfe D, Mata M, Huang S, Glorioso JC, Fink DJ . Long-term neuroprotection achieved with latency-associated promoter-driven herpes simplex virus gene transfer to the peripheral nervous system. Mol Ther 2005; 12: 307–313.

    Article  CAS  PubMed  Google Scholar 

  12. Chattopadhyay M, Goss J, Wolfe D, Goins WC, Huang S, Glorioso JC et al. Protective effect of herpes simplex virus-mediated neurotrophin gene transfer in cisplatin neuropathy. Brain 2004; 127 (Part 4): 929–939.

    Article  PubMed  Google Scholar 

  13. Chattopadhyay M, Krisky D, Wolfe D, Glorioso JC, Mata M, Fink DJ . HSV-mediated gene transfer of vascular endothelial growth factor to dorsal root ganglia prevents diabetic neuropathy. Gene Therapy 2005; 12: 1377–1384.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Chattopadhyay M, Mata M, Goss J, Wolfe D, Huang S, Glorioso JC et al. Prolonged preservation of nerve function in diabetic neuropathy in mice by herpes simplex virus-mediated gene transfer. Diabetologia 2007; 50: 1550–1558.

    Article  CAS  PubMed  Google Scholar 

  15. Chattopadhyay M, Walter C, Mata M, Fink DJ . Neuroprotective effect of herpes simplex virus-mediated gene transfer of erythropoietin in hyperglycemic dorsal root ganglion neurons. Brain 2009; 132 (Part 4): 879–888.

    PubMed  PubMed Central  Google Scholar 

  16. Puskovic V, Wolfe D, Goss J, Huang S, Mata M, Glorioso JC et al. Prolonged biologically active transgene expression driven by HSV LAP2 in brain in vivo. Mol Ther 2004; 10: 67–75.

    Article  CAS  PubMed  Google Scholar 

  17. Wu Z, Mata M, Fink DJ . Prevention of diabetic neuropathy by regulatable expression of HSV-mediated erythropoietin. Mol Ther 2011; 19: 310–317.

    Article  CAS  PubMed  Google Scholar 

  18. Goins WF, Sternberg LR, Croen KD, Krause PR, Hendricks RL, Fink DJ et al. A novel latency-active promoter is contained within the herpes simplex virus type 1 UL flanking repeats. J Virol 1994; 68: 2239–2252.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Shuai H, Zhang J, Zhang J, Xie J, Zhang M, Yu Y et al. Erythropoietin protects pancreatic beta-cell line NIT-1 cells against cytokine-induced apoptosis via phosphatidylinositol 3-kinase/Akt signaling. Endocr Res 2011; 36: 25–34.

    Article  CAS  PubMed  Google Scholar 

  20. Dang J, Jia R, Tu Y, Xiao S, Ding G . Erythropoietin prevents reactive oxygen species generation and renal tubular cell apoptosis at high glucose level. Biomed Pharmacother 2010; 64: 681–685.

    Article  CAS  PubMed  Google Scholar 

  21. Cervellini I, Bello E, Frapolli R, Porretta-Serapiglia C, Oggioni N, Canta A et al. The neuroprotective effect of erythropoietin in docetaxel-induced peripheral neuropathy causes no reduction of antitumor activity in 13762 adenocarcinoma-bearing rats. Neurotox Res 2010; 18: 151–160.

    Article  CAS  PubMed  Google Scholar 

  22. Schmidt RE, Green KG, Feng D, Dorsey DA, Parvin CA, Lee JM et al. Erythropoietin and its carbamylated derivative prevent the development of experimental diabetic autonomic neuropathy in STZ-induced diabetic NOD-SCID mice. Exp Neurol 2008; 209: 161–170.

    Article  CAS  PubMed  Google Scholar 

  23. Melli G, Jack C, Lambrinos GL, Ringkamp M, Höke A . Erythropoietin protects sensory axons against paclitaxel-induced distal degeneration. Neurobiol Dis 2006; 24: 525–530.

    Article  CAS  PubMed  Google Scholar 

  24. Stieger K, Mendes-Madeira A, Meur GL, Weber M, Deschamps JY, Nivard D et al. Oral administration of doxycycline allows tight control of transgene expression: a key step towards gene therapy of retinal diseases. Gene Therapy 2007; 14: 1668–1673.

    Article  CAS  PubMed  Google Scholar 

  25. McGee Sanftner LH, Rendahl KG, Quiroz D, Coyne M, Ladner M, Manning WC et al. Recombinant AAV-mediated delivery of a tet-inducible reporter gene to the rat retina. Mol Ther 2001; 3 (5 Part 1): 688–696.

    Article  CAS  PubMed  Google Scholar 

  26. Gossen M, Bujard H . Tight control of gene expression in mammalian cells by tetracycline-responsive promoters. Proc Natl Acad Sci USA 1992; 89: 5547–5551.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Gossen M, Freundlieb S, Bender G, Müller G, Hillen W, Bujard H . Transcriptional activation by tetracyclines in mammalian cells. Science 1995; 268: 1766–1769.

    Article  CAS  PubMed  Google Scholar 

  28. Yao F, Svensjö T, Winkler T, Lu M, Eriksson C, Eriksson E . Tetracycline repressor, tetR, rather than the tetR-mammalian cell transcription factor fusion derivatives, regulates inducible gene expression in mammalian cells. Hum Gene Ther 1998; 9: 1939–1950.

    Article  CAS  PubMed  Google Scholar 

  29. Muhammad AK, Puntel M, Candolfi M, Salem A, Yagiz K, Farrokhi C et al. Study of the efficacy, biodistribution, and safety profile of therapeutic gutless adenovirus vectors as a prelude to a phase I clinical trial for glioblastoma. Clin Pharmacol Ther 2010; 88: 204–213.

    Article  CAS  PubMed  Google Scholar 

  30. Xiong W, Candolfi M, Kroeger KM, Puntel M, Mondkar S, Larocque D et al. Immunization against the transgene but not the TetON switch reduces expression from gutless adenoviral vectors in the brain. Mol Ther 2008; 16: 343–351.

    Article  CAS  PubMed  Google Scholar 

  31. Stieger K, Belbellaa B, Le Guiner C, Moullier P, Rolling F . In vivo gene regulation using tetracycline-regulatable systems. Adv Drug Deliv Rev 2009; 61: 527–541.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Barde I, Zanta-Boussif MA, Paisant S, Leboeuf M, Rameau P, Delenda C et al. Efficient control of gene expression in the hematopoietic system using a single Tet-on inducible lentiviral vector. Mol Ther 2006; 13: 382–390.

    Article  CAS  PubMed  Google Scholar 

  33. Favre D, Blouin V, Provost N, Spisek R, Porrot F, Bohl D et al. Lack of an immune response against the tetracycline-dependent transactivator correlates with long-term doxycycline-regulated transgene expression in nonhuman primates after intramuscular injection of recombinant adeno-associated virus. J Virol 2002; 76: 11605–11611.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Stieger K, Le Meur G, Lasne F, Weber M, Deschamps JY, Nivard D et al. Long-term doxycycline-regulated transgene expression in the retina of nonhuman primates following subretinal injection of recombinant AAV vectors. Mol Ther 2006; 13: 967–975.

    Article  CAS  PubMed  Google Scholar 

  35. Stevens JG . Human herpesvisruses: a consideration of the latent state. Microbiol Rev 1989; 53: 318–332.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Puskovic V, Wolfe D, Wechuck J, Krisky D, Collins J, Glorioso JC et al. HSV-mediated delivery of erythropoietin restores dopaminergic function in MPTP-treated mice. Mol Ther 2006; 14: 710–715.

    Article  CAS  PubMed  Google Scholar 

  37. Fink DJ, Wechuck J, Mata M, Glorioso JC, Goss J, Krisky D et al. Gene therapy for pain: results of a phase I clinical trial. Ann Neurol 2011; 70: 207–212.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Parris DS, Harrington JE . Herpes simplex virus variants restraint to high concentrations of acyclovir exist in clinical isolates. Antimicrob Agents Chemother 1982; 22: 71–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors acknowledge the assistance of Vikram Thakur in vector propagation, and Jesssica Myers for help in conducting electrophysiolgy testing. The work was supported by NIH grants DK044935 and NS038850, and grants from the Department of Veterans Affairs and the Juvenile Diabetes Research Foundation.

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  1. Department of Neurology, University of Michigan and VA Ann Arbor Healthcare System, Ann Arbor, MI, USA

    Z Wu, M Mata & D J Fink

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Correspondence to D J Fink.

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Wu, Z., Mata, M. & Fink, D. Prolonged regulatable expression of EPO from an HSV vector using the LAP2 promoter element. Gene Ther 19, 1107–1113 (2012). https://doi.org/10.1038/gt.2011.188

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