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NeuroRX

, Volume 2, Issue 1, pp 129–138 | Cite as

Tyrosine hydroxylase replacement in experimental Parkinson’s disease with transvascular gene therapy

  • William M. Pardridge
Article

Summary

Transvascular gene therapy of Parkinson’s disease (PD) is a new approach to the gene therapy of PD and involves the global distribution of a therapeutic gene to brain after an intravenous administration and transport across the blood-brain barrier (BBB). This is enabled with the development of a nonviral gene transfer technology that encapsulates plasmid DNA inside pegylated immunoliposomes or PILs. An 85- to 100-nm liposome carries the DNA inside the nanocontainer, and the liposome surface is conjugated with several thousand strands of 2000-Da polyethyleneglycol (PEG). This PEGylation of the liposome stabilizes the structure in the blood stream. The liposome is targeted across the BBB via attachment to the tips of 1–2% of the PEG strands of a receptor-specific monoclonal antibody (mAb) directed at a BBB receptor, such as the insulin receptor or transferrin receptor (TfR). Owing to the expression of the insulin receptor or the TfR on both the BBB and the neuronal plasma membrane, the PIL is able to reach the neuronal nuclear compartment from the circulation. Brain-specific expression is possible with the combined use of the PIL gene transfer technology and brain-specific gene promoters. In the 6-hydroxydopamine rat model of experimental PD, striatal tyrosine hydroxylase (TH) activity is completely normalized after an intravenous administration of TfRmAb-targeted PILs carrying a TH expression plasmid. A treatment for PD may be possible with dual gene therapy that seeks both to replace striatal TH gene expression with TH gene therapy, and to halt or reverse neurodegeneration of the nigro-striatal tract with neurotrophin gene therapy.

Key Words

Blood-brain barrier liposomes transferrin receptor monoclonal antibody targeting 

References

  1. 1.
    Shastry BS. Parkinson disease: etiology, pathogenesis and future of gene therapy.Neurosci Res 41: 5–12, 2001.PubMedCrossRefGoogle Scholar
  2. 2.
    Booij J, Bergmans P, Winogrodzka A, Speelman JD, Wolters EC. Imaging of dopamine transporters with [123I]FP-CIT SPECT does not suggest a significant effect of age on the symptomatic threshold of disease in Parkinson’s disease.Synapse 39: 101–108, 2001.PubMedCrossRefGoogle Scholar
  3. 3.
    Boado RJ, Li JY, Nagaya M, Zhang C, Pardridge WM. Selective expression of the large neutral amino acid transporter at the blood-brain barrier.Proc Natl Acad Sci USA 96: 12079–12084, 1999.PubMedCrossRefGoogle Scholar
  4. 4.
    Kordower JH, Emborg ME, Bloch J, Ma SY, Chu Y, Leventhal L, et al. Neurodegeneration prevented by lentiviral vector delivery of GDNF in primate models of Parkinson’s disease.Science 290: 767–773, 2000.PubMedCrossRefGoogle Scholar
  5. 5.
    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: implications for clinical trials.Nat Med 5: 1256–1263, 1999.PubMedCrossRefGoogle Scholar
  6. 6.
    McMenamin MM, Byrnes AP, Charlton HM, Coffin RS, Latchman DS, Wood MJ. A γ34.5 mutant of herpes simplex 1 causes severe inflammation in the brain.Neuroscience 83: 1225–1237, 1998.PubMedCrossRefGoogle Scholar
  7. 7.
    Chirmule N, Propert K, Magosin S, Qian Y, Qian R, Wilson J. Immune responses to adenovirus and adeno-associated virus in humans.Gene Ther 6: 1574–1583, 1999.PubMedCrossRefGoogle Scholar
  8. 8.
    Miller DG, Rutledge EA, Russell DW. Chromosomal effects of adeno-associated virus vector integration.Nat Genet 30: 147–148, 2002.PubMedCrossRefGoogle Scholar
  9. 9.
    Laufs S, Gentner B, Nagy KZ, Jauch A, Benner A, Naundorf S, et al. Retroviral vector integration occurs in preferred genomic targets of human bone marrow-repopulating cells.Blood 101: 2191–2198, 2003.PubMedCrossRefGoogle Scholar
  10. 10.
    Ai Y, Markesbery W, Zhang Z, Grondin R, Elseberry D, Gerhardt GA, et al. Intraputamenal infusion of GDNF in aged rhesus monkeys: distribution and dopaminergic effects.J Comp Neurol 461: 250–261, 2003.PubMedCrossRefGoogle Scholar
  11. 11.
    Pardridge WM. Drug and gene targeting to the brain with molecular Trojan horses.Nat Rev Drug Discov 1: 131–139, 2002.PubMedCrossRefGoogle Scholar
  12. 12.
    Shi N, Pardridge WM. Non-invasive gene targeting to the brain.Proc Natl Acad Sci USA 97: 7567–7572, 2000.PubMedCrossRefGoogle Scholar
  13. 13.
    Huwyler J, Wu D, Pardridge WM. Brain drug delivery of small molecules using immunoliposomes.Proc Natl Acad Sci USA 93: 14164–14169, 1996.PubMedCrossRefGoogle Scholar
  14. 14.
    Zhang Y, Calon F, Zhu C, Boado RJ, Pardridge WM. Intravenous nonviral gene therapy causes normalization of striatal tyrosine hydroxylase and reversal of motor impairment in experimental parkinsonism.Hum Gene Ther 14: 1–12, 2003.PubMedCrossRefGoogle Scholar
  15. 15.
    Plank C, Tang MX, Wolfe AR, Szoka FC Jr. Branched cationic peptides for gene delivery: role of type and number of cationic residues in formation and in vitro activity of DNA polyplexes.Hum Gene Ther 10: 319–332, 1999.PubMedCrossRefGoogle Scholar
  16. 16.
    Hong K, Zheng W, Baker A, Papahadjopoulos D. Stabilization of cationic liposome-plasmid DNA complexes by polyamines and poly(ethylene glycol)-phospholipid conjugates for efficient in vivo gene delivery.FEBS Lett 400: 233–237, 1997.PubMedCrossRefGoogle Scholar
  17. 17.
    Osaka G, Carey K, Cuthbertson A, Godowski P, Patapoff T, Ryan A, et al. Pharmacokinetics, tissue distribution, and expression efficiency of plasmid [33P]DNA following intravenous administration of DNA/cationic lipid complexes in mice: use of a novel radionuclide approach.J Pharm Sci 85: 612–618, 1996.PubMedCrossRefGoogle Scholar
  18. 18.
    Shi N, Zhang Y, Zhu C, Boado RJ, Pardridge WM. Brain-specific expression of an exogenous gene after i.v. administration.Proc Natl Acad Sci USA 98: 12754–12759, 2001.PubMedCrossRefGoogle Scholar
  19. 19.
    Zhang Y, Schlachetzki F, Pardridge WM. Global non-viral gene transfer to the primate brain following intravenous administration.Mol Ther 7: 11–18, 2003.PubMedCrossRefGoogle Scholar
  20. 20.
    Zhang Y, Jeong Lee H, Boado RJ, Pardridge WM. Receptor-mediated delivery of an antisense gene to human brain cancer cells.J Gene Med 4: 183–194, 2002.PubMedCrossRefGoogle Scholar
  21. 21.
    Pardridge WM, Kang YS, Buciak JL, Yang J. Human insulin receptor monoclonal antibody undergoes high affinity binding to human brain capillaries in vitro and rapid transcytosis through the blood-brain barrier in vivo in the primate.Pharm Res 12: 807–816, 1995.PubMedCrossRefGoogle Scholar
  22. 22.
    Shi N, Boado RJ, Pardridge WM. Receptor-mediated gene targeting to tissues in vivo following intravenous administration of pe-gylated immunoliposomes.Pharm Res 18: 1091–1095, 2001.PubMedCrossRefGoogle Scholar
  23. 23.
    Zhang Y, Boado RJ, Pardridge WM. Marked enhancement in gene expression by targeting the human insulin receptor.J Gene Med 5: 157–163, 2003.PubMedCrossRefGoogle Scholar
  24. 24.
    Zhang Y, Schlachetzki F, Li JY, Boado RJ, Pardridge WM. Organ-specific gene expression in the rhesus monkey eye following intravenous non-viral gene transfer.Mol Vis 9: 465–472, 2003.PubMedGoogle Scholar
  25. 25.
    Zhang Y, Schlachetzki F, Zhang YF, Boado RJ, Pardridge WM. Normalization of striatal tyrosine hydroxylase and reversal of motor impairment in experimental parkinsonism with intravenous nonviral gene therapy and a brain-specific promoter.Hum Gene Ther 15: 339–350, 2004.PubMedCrossRefGoogle Scholar
  26. 26.
    Vann LR, Payne SG, Edsall LC, Twitty S, Spiegel S, Milstien S. Involvement of sphingosine kinase in TNF-α-stimulated tetrahy-drobiopterin biosynthesis in C6 glioma cells.J Biol Chem 277: 12649–12656, 2002.PubMedCrossRefGoogle Scholar
  27. 27.
    Nussler AK, Liu ZZ, Hatakeyama K, Geller DA, Billiar TR, Morris SM Jr. A cohort of supporting metabolic enzymes is coinduced with nitric oxide synthase in human tumor cell lines.Cancer Lett 103: 79–84, 1996.PubMedCrossRefGoogle Scholar
  28. 28.
    Nagatsu I, Ichinose H, Sakai M, Titani K, Suzuki M, Nagatsu T. Immunocytochemical localization of GTP cyclohydrolase I in the brain, adrenal gland, and liver of mice.J Neural Transm Gen Sect 102: 175–188, 1995.PubMedCrossRefGoogle Scholar
  29. 29.
    Shimoji M, Hirayama K, Hyland K, Kapatos G. GTP cyclohydrolase I gene expression in the brains of male and female hph-1 mice.J Neurochem 72: 757–764, 1999.PubMedCrossRefGoogle Scholar
  30. 30.
    Palish CL, Finkelstein DI, Tripanichkul W, Satoskar AR, Drago J, Home MK. The role of interleukin-1, interleukin-6, and glia in inducing growth of neuronal terminal arbors in mice.J Neurosci 22: 8034–8041, 2002.Google Scholar
  31. 31.
    Stanic D, Finkelstein DI, Bourke DW, Drago J, Horne MK. Time-course of striatal re-innervation following lesions of dopaminergic SNpc neurons of the rat.Eur J Neurosci 18: 1175–1188, 2003.PubMedCrossRefGoogle Scholar
  32. 32.
    Kozlowski DA, Connor B, Tillerson JL, Schallert T, Bohn MC. Delivery of a GDNF gene into the substantia nigra after a progressive 6-OHDA lesion maintains functional nigrostriatal connections.Exp Neurol 166: 1–15, 2000.PubMedCrossRefGoogle Scholar
  33. 33.
    Levine RA, Miller LP, Lovenberg W. Tetrahydrobiopterin in striatum: localization in dopamine nerve terminals and role in cate-cholamine synthesis.Science 214: 919–921, 1981.PubMedCrossRefGoogle Scholar
  34. 34.
    Kaneda N, Sasaoka T, Kobayashi K, Kiuchi K, Nagatsu I, Kurosawa Y, et al. Tissue-specific and high-level expression of the human tyrosine hydroxylase gene in transgenic mice.Neuron 6: 583–594, 1991.PubMedCrossRefGoogle Scholar
  35. 35.
    Segovia J, Vergara P, Brenner M. Astrocyte-specific expression of tyrosine hydroxylase after intracerebral gene transfer induces behavioral recovery in experimental parkinsonismGene Ther 5: 1650–1655, 1998.PubMedCrossRefGoogle Scholar
  36. 36.
    Bell H, Kimber WL, Li M, Whittle IR. Liposomal transfection efficiency and toxicity on glioma cell lines: in vitro and in vivo studies.Neuroreport 9: 793–798, 1998.PubMedCrossRefGoogle Scholar
  37. 37.
    Foster JA, Christopherson PL, Levine RA. GTP cyclohydrolase I induction in striatal astrocytes following intrastriatal kainic acid lesion.J Chem Neuroanat 24: 173–179, 2002.PubMedCrossRefGoogle Scholar
  38. 38.
    Kaneko R, Sueoka N. Tissue-specific versus cell type-specific expression of the glial fibrillary acidic protein.Proc Nail Acad Sci USA 90: 4698–4702, 1993.CrossRefGoogle Scholar
  39. 39.
    Galou M, Pournin S, Ensergueix D, Ridet JL, Tchelingerian JL, Lossouam L, et al. Normal and pathological expression of GFAP promoter elements in transgenic mice.Glia 12: 281–293, 1994.PubMedCrossRefGoogle Scholar
  40. 40.
    Zhuo L, Theis M, Alvarez-Maya I, Brenner M, Willecke K, Messing A. hGFAP-cre transgenic mice for manipulation of glial and neuronal function in vivo.Genesis 31: 85–94, 2001.PubMedCrossRefGoogle Scholar
  41. 41.
    Gomes FC, Garcia-Abreu J, Galou M, Paulin D, Moura Neto V. Neurons induce GFAP gene promoter of cultured astrocytes from transgenic mice.Glia 26: 97–108, 1999.PubMedCrossRefGoogle Scholar
  42. 42.
    Coloma MJ, Lee HJ, Kurihara A, Landaw EM, Boado RJ, Morrison SL, et al. Transport across the primate blood-brain barrier of a genetically engineered chimeric monoclonal antibody to the human insulin receptor.Pharm Res 17: 266–274, 2000.PubMedCrossRefGoogle Scholar
  43. 43.
    Zhang YF, Boado RJ, Pardridge WM. Absence of toxicity of chronic weekly intravenous gene therapy with pegylated immunoliposomes.Pharm Res 20: 1779–1785, 2003.PubMedCrossRefGoogle Scholar

Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc 2005

Authors and Affiliations

  1. 1.Department of MedicineUCLALos Angeles

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