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Prevention of onset of Parkinson’s disease by in vivo gene transfer of human hepatocyte growth factor in rodent model: a model of gene therapy for Parkinson’s disease

Abstract

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra (SNi). As neurotrophic factors support the survival and enhance the function of dopaminergic neurons, gene therapy using neurotrophic factors has become the center of interest. Thus, we focused on hepatocyte growth factor (HGF) as a neurotrophic and angiogenic growth factor. At 7 days before injection of 6-hydroxydopamine into the SNi, stereotaxic transfection of human HGF or lacZ plasmid was performed into the unilateral striatum of rats. Expression of human HGF in the injected sites could be detected in rats transfected with HGF plasmid DNA, using immunohistochemical staining. Consistently, human immunoreactive HGF protein could be detected at least up to 12 days after transfection. Interestingly, PD rats transfected with lacZ demonstrated amphetamine-induced rotational asymmetry. However, transfection of HGF plasmid DNA resulted in significant inhibition of abnormal rotation up to 24 weeks in a dose-dependent manner. Over 90% of dopaminergic neurons were lost in PD rats transfected with lacZ, whereas over 70% survived in rats transfected with HGF, as assessed by immunohistochemical staining. Overall, the present study demonstrated that overexpression of HGF prevented neuronal death in a PD rat model, providing a potential novel therapy for PD.

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References

  1. Eck SL, Alavi JB, Judy K, Phillips P, Alavi A, Hackney D et al. Treatment of recurrent or progressive malignant glioma with a recombinant adenovirus expressing human interferon-beta (H5.010CMVhINF-beta): a phase I trial. Hum Gene Ther 2001; 12: 97–113.

    Article  CAS  Google Scholar 

  2. Trask TW, Trask RP, Aguilar-Cordova F, Shine HD, Wyde PR, Goodman JC et al. Phase I study of adenoviral delivery of the HSK-tk gene and ganciclovir administration in patients with current malignant brain tumors. Mol Ther 2000; 1: 195–203.

    Article  CAS  Google Scholar 

  3. During MJ, Kaplitt MG, Stern MB, Eidelberg D . Subthalamic GAD gene transfer in Parkinson’s disease patients who are candidates for deep brain stimulation. Hum Gene Ther 2001; 12: 1589–1591.

    CAS  Google Scholar 

  4. Janson C, McPhee S, Bilaniuk L, Haselgrove J, Testaiuti M, Freese A et al. Clinical protocol. Gene Therapy of Canavan disease: AAV-2 vector for neurosurgical delivery of aspartoacylase gene (ASPA) to the human brain. Hum Gene Ther 2002; 13: 1391–1412.

    Article  CAS  Google Scholar 

  5. Shastry BS . Parkinson’s disease: etiology, pathogenesis and future of gene therapy. Neurosci Res 2001; 41: 5–12.

    Article  CAS  Google Scholar 

  6. Henningson Jr CT, Stanislaus MA, Gewirtz MA . Embryonic and adult stem cell therapy. J Allergy Clin Immunol 2003; 111 (Suppl. 2): S745–S753.

    Article  Google Scholar 

  7. Simpkinsn N, Jankovic J . Neuroprotection in Parkinson disease. Arch Intern Med 2003; 163: 1650–1654.

    Article  Google Scholar 

  8. Hurelbrink CB, Barker RA . Prospects for the treatment of Parkinson’s disease using neurotrophic factor. Expert Opin Pharmacother 2001; 2: 1531–1543.

    Article  CAS  Google Scholar 

  9. Wang L, Muramatsu S, Lu Y, Ikeguchi K, Fujimoto K, Okada T et al. Delayed delivery of AAV-GDNF prevents nigral neurodegeneration and promotes functional recovery in a rat model of Parkinson’s disease. Gene Therapy 2002; 9: 381–399.

    Article  CAS  Google Scholar 

  10. Bensadoun JC, Deglon N, Tseng JL, Ridet JL, Zurn AD, Aebischer P . Lentiviral vectors as a gene delivery system in the mouse midbrain: cellular and behavioral improvements in a 6-OHDA model of Parkinson’s disease using GDNF. Exp Neurol 2000; 164: 15–24.

    Article  CAS  Google Scholar 

  11. Yasuhara T, Shingo T, Muraoka K, Wen Ji Y, Kameda M, Takeuchi A et al. The differences between high and low-dose administration of VEGF to dopaminergic neurons of in vitro and in vivo Parkinson’s disease model. Brain Res 2005; 1038: 1–10.

    Article  CAS  Google Scholar 

  12. Nakamura T, Nishizawa T, Hagiya M, Seki T, Shimonishi M, Sugimura A et al. Molecular cloning and expression of human hepatocyte growth factor. Nature 1989; 342: 440–443.

    Article  CAS  Google Scholar 

  13. Sun W, Funakoshi H, Nakamura T . Overexpression of HGF retards disease progression and prolongs life span in a transgenic mouse model of ALS. J Neurosci 2002; 22: 6537–6548.

    Article  CAS  Google Scholar 

  14. Miyazawa T, Matsumoto K, Ohmichi H, Yamashima T, Chigasaki H, Nakamura T . Protection of hippocampal neurons from ischemia-induced delayed neuronal death by hepatocyte growth factor: a novel neurotrophic factor. J Celebral Blood Flow Metab 1998; 18: 345–348.

    Article  CAS  Google Scholar 

  15. Date I, Takagi N, Takagi K, Kago T, Matsumoto K, Nakamura T et al. Hepatocyte growth factor improved learning and memory dysfunction of microsphene embolized rats. J Neurosci Res 2004; 78: 442–453.

    Article  CAS  Google Scholar 

  16. Hamanoue M, Takemoto N, Matsumoto K, Nakamura T, Nakajima K, Kohsaka S . Neurotrophic effect of hepatocyte growth factor on central nervous system neurons in vitro. J Neurosci Res 1996; 43: 554–564.

    Article  CAS  Google Scholar 

  17. Koike H, Morishita R, Iguchi S, Aoki M, Matsumoto K, Nakamura T et al. Enhanced angiogenesis and improvement of neuropathy by cotransfection of human hepatocyte growth factor and prostacyclin synthase gene. FASEB J 2003; 17: 779–781.

    Article  CAS  Google Scholar 

  18. Tomita N, Morishita R, Taniyama Y, Koike H, Aoki M, Shimizu H et al. Angiogenic property of hepatocyte growth factor is dependent on upregulation of essential transcription factor for angiogenesis, ets-1. Circulation 2003; 107: 1411–1417.

    Article  CAS  Google Scholar 

  19. Morishita R . Recent progress in gene therapy for cardiovascular disease. Circ J 2002; 66: 1077–1086.

    Article  CAS  Google Scholar 

  20. Maina F, Klein R . Hepatocyte growth factor, a versatile signal for developing neurons. Nat Neurosci 1999; 2: 213–217.

    Article  CAS  Google Scholar 

  21. Schnell MA, Zhang Y, Tazelaar J, Gao GP, Yu QC, Qian R et al. Activation of innate immunity in nonhuman primates following intraportal administration of adenoviral vectors. Mol Ther 2001; 3: 708–722.

    Article  CAS  Google Scholar 

  22. Dewey RA, Morrissey G, Cowsill CM, Stone D, Bolognani F, Dodd NJ et al. Chronic brain inflammation and persistent herpes simplex virus 1 thymidine kinase expression in survivors of syngeneic glioma treated by adenovirus-mediated gene therapy: implication for clinical trial. Nat Med 1999; 5: 1256–1263.

    Article  CAS  Google Scholar 

  23. Hsich G, Sena-Esteves M, Breakfield XO . Critical issues in gene therapy for neurologic disease. Hum Gene Ther 2002; 13: 579–604.

    Article  CAS  Google Scholar 

  24. Gill SS, Patel NK, Hotton GR, O’Sullivan K, McCarter R, Bunnage M et al. Direct brain of glial cell line-derived neurotrophic factor in Parkinson disease. Nat Med 2003; 9: 589–595.

    Article  CAS  Google Scholar 

  25. Honda S, Kagoshima M, Wanaka A, Tohyama M, Matsumoto K, Nakamura T . Localization and functional coupling of HGF and c-Met/HGF receptor in rat brain: implication as neurotrophic factor. Mol Brain Res 1995; 32: 197–210.

    Article  CAS  Google Scholar 

  26. Zhang L, Himi T, Morita I, Murota S . Hepatocyte growth factor protects cultured rat cerebellar granule neurons from apoptosis via the phosphatidylinositol-3 kinase/Akt pathway. J Neurosci Res 2000; 59: 489–496.

    Article  CAS  Google Scholar 

  27. Davey F, Hilton M, Davies AM . Cooperation between HGF and CNTF in promoting the survival and growth of sensory and parasympathetic neurons. Mol Cell Neurosci 2000; 15: 79–87.

    Article  CAS  Google Scholar 

  28. Hayashi K, Morishita R, Nakagami H, Yoshimura S, Hara A, Matsumoto K et al. Gene therapy for preventing neuronal death using hepatocyte growth factor: in vivo gene transfer of HGF to subarachnoid space prevents delayed neuronal death in gerbil hippocampal CA1 neurons. Gene Therapy 2001; 8: 1167–1173.

    Article  CAS  Google Scholar 

  29. Baumgartner I, Rauh G, Pieczek A, Wuensch D, Magner M, Kearney M et al. Lower-extremity edema associated with gene transfer of naked DNA encoding vascular endothelial growth factor. Ann Intern Med 2000; 132: 880–884.

    Article  CAS  Google Scholar 

  30. Vale PR, Losordo DW, Milliken CE, Maysky M, Esakof DD, Symes JF et al. Left ventricular electromechanical mapping to assess efficacy of phVEGF165 gene transfer for therapeutic angiogenesis in chronic myocardial ischemia. Circulation 2000; 102: 965–974.

    Article  CAS  Google Scholar 

  31. Morishita R, Aoki M, Hashiya N, Makino H, Yamasaki K, Azuma J et al. Safety evaluation of clinical gene therapy using hepatocyte growth factor to treat peripheral arterial disease by therapeutic angiogenesis. Hypertension 2004; 44: 203–209.

    Article  CAS  Google Scholar 

  32. Schwartz B, Benoist C, Abdallah B, Rangara R, Hassan A, Scherman D et al. Gene transfer by naked DNA into adult mouse brain. Gene Therapy 1996; 3: 405–411.

    CAS  Google Scholar 

  33. Sekiguchi K, Yasuzumi F, Morishita R . Exogenous expression of hepatocyte growth factor (HGF) in rat striatum by naked plasmid DNA. Neurosci Res 2003; 45: 173–180.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was partially supported by a Grant-in-Aid from the Organization for Pharmaceutical Safety and Research, a Grant-in-Aid from The Ministry of Public Health and Welfare, a Grant-in-Aid from Japan Promotion of Science, and through Special Coordination Funds of the Ministry of Education, Culture, Sports, Science and Technology, the Japanese Government.

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Correspondence to R Morishita.

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Koike, H., Ishida, A., Shimamura, M. et al. Prevention of onset of Parkinson’s disease by in vivo gene transfer of human hepatocyte growth factor in rodent model: a model of gene therapy for Parkinson’s disease. Gene Ther 13, 1639–1644 (2006). https://doi.org/10.1038/sj.gt.3302810

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