title: Tyrosine hydroxylase replacement in experimental Parkinson's disease with transvascular gene therapy.
abstract: 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.
authors.affiliation: Department of Medicine, UCLA, Los Angeles, California 90024, USA. wpardridge@mednet.ucla.edu
authors.forename: William M
authors.initials: WM
authors.lastname: Pardridge
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier; D015316:Genetic Therapy; D006801:Humans; D008081:Liposomes; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000235:genetics / Q000628:therapy*; D011092:Polyethylene Glycols; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000627:therapeutic use*
chemical_list: D008081:Liposomes; D011092:Polyethylene Glycols; D014446:Tyrosine 3-Monooxygenase
references.citation: Science. 2000 Oct 27;290(5492):767-73
references.pmid: 11052933
references.citation: Pharm Res. 1995 Jun;12(6):807-16
references.pmid: 7667183
references.citation: Neurosci Res. 2001 Sep;41(1):5-12
references.pmid: 11535288
references.citation: Pharm Res. 2001 Aug;18(8):1091-5
references.pmid: 11587478
references.citation: Genesis. 2001 Oct;31(2):85-94
references.pmid: 11668683
references.citation: Proc Natl Acad Sci U S A. 2001 Oct 23;98(22):12754-9
references.pmid: 11592987
references.citation: Nat Genet. 2002 Feb;30(2):147-8
references.pmid: 11799395
references.citation: J Gene Med. 2002 Mar-Apr;4(2):183-94
references.pmid: 11933219
references.citation: J Biol Chem. 2002 Apr 12;277(15):12649-56
references.pmid: 11815603
references.citation: Nat Rev Drug Discov. 2002 Feb;1(2):131-9
references.pmid: 12120094
references.citation: J Neurosci. 2002 Sep 15;22(18):8034-41
references.pmid: 12223557
references.citation: Cancer Lett. 1996 May 15;103(1):79-84
references.pmid: 8616812
references.citation: J Pharm Sci. 1996 Jun;85(6):612-8
references.pmid: 8773958
references.citation: Nat Med. 1999 Nov;5(11):1256-63
references.pmid: 10545991
references.citation: Pharm Res. 2000 Mar;17(3):266-74
references.pmid: 10801214
references.citation: Proc Natl Acad Sci U S A. 2000 Jun 20;97(13):7567-72
references.pmid: 10840060
references.citation: Exp Neurol. 2000 Nov;166(1):1-15
references.pmid: 11031079
references.citation: J Neural Transm Gen Sect. 1995;102(3):175-188
references.pmid: 8788067
references.citation: Proc Natl Acad Sci U S A. 1996 Nov 26;93(24):14164-9
references.pmid: 8943078
references.citation: FEBS Lett. 1997 Jan 3;400(2):233-7
references.pmid: 9001404
references.citation: Neuroscience. 1998 Apr;83(4):1225-37
references.pmid: 9502260
references.citation: Neuroreport. 1998 Mar 30;9(5):793-8
references.pmid: 9579667
references.citation: J Neurochem. 1999 Feb;72(2):757-64
references.pmid: 9930750
references.citation: Hum Gene Ther. 1999 Jan 20;10(2):319-32
references.pmid: 10022556
references.citation: Gene Ther. 1998 Dec;5(12):1650-5
references.pmid: 10023444
references.citation: Glia. 1999 Apr;26(2):97-108
references.pmid: 10384875
references.citation: Gene Ther. 1999 Sep;6(9):1574-83
references.pmid: 10490767
references.citation: Proc Natl Acad Sci U S A. 1999 Oct 12;96(21):12079-84
references.pmid: 10518579
references.citation: J Chem Neuroanat. 2002 Sep;24(3):173-9
references.pmid: 12297263
references.citation: J Gene Med. 2003 Feb;5(2):157-63
references.pmid: 12539153
references.citation: Hum Gene Ther. 2003 Jan 1;14(1):1-12
references.pmid: 12573054
references.citation: Mol Ther. 2003 Jan;7(1):11-8
references.pmid: 12573613
references.citation: Blood. 2003 Mar 15;101(6):2191-8
references.pmid: 12424203
references.citation: J Comp Neurol. 2003 Jun 23;461(2):250-61
references.pmid: 12724841
references.citation: Eur J Neurosci. 2003 Sep;18(5):1175-88
references.pmid: 12956716
references.citation: Mol Vis. 2003 Oct 3;9:465-72
references.pmid: 14551536
references.citation: Pharm Res. 2003 Nov;20(11):1779-85
references.pmid: 14661922
references.citation: Hum Gene Ther. 2004 Apr;15(4):339-50
references.pmid: 15053859
references.citation: Science. 1981 Nov 20;214(4523):919-21
references.pmid: 6117945
references.citation: Neuron. 1991 Apr;6(4):583-94
references.pmid: 1673055
references.citation: Proc Natl Acad Sci U S A. 1993 May 15;90(10):4698-702
references.pmid: 8506321
references.citation: Glia. 1994 Dec;12(4):281-93
references.pmid: 7890332
references.citation: Synapse. 2001 Feb;39(2):101-8
references.pmid: 11180497