Advertisement

Delivery Strategies for RNAi to the Nervous System

  • Kevin D. Foust
  • Brian K. KasparEmail author
Protocol
  • 704 Downloads
Part of the Neuromethods book series (NM, volume 58)

Abstract

Drug and gene delivery to the central nervous system poses significant challenges to basic researchers and clinicians. The blood–brain barrier prevents most substances from reaching the desired target cells. Strategies for RNA interference (RNAi) have been proposed for certain neurological disorders in order to suppress a toxic protein and, therefore, stop neurodegeneration or slow disease progression. Nucleic acid delivery strategies have been employed in numerous models, demonstrating significant promise including the delivery of RNAi. However, delivery challenges for RNAi exist similar to those for drug and gene delivery platforms, such as the effective delivery to the region or regional areas of the brain and spinal cord affected in disease. Additionally, the persistence of RNAi may need to be long term. This review provides the reader with current data on challenges of RNAi delivery, with important considerations in the design of effective delivery strategies, which encompass nonviral and viral strategies.

Key words

Gene delivery Central nervous system Blood–brain barrier Viral Nonviral Gene therapy 

References

  1. 1.
    Behlke MA. Chemical modification of siRNAs for in vivo use. Oligonucleotides 2008;18(4):305–19.PubMedGoogle Scholar
  2. 2.
    Watts JK, Deleavey GF, Damha MJ. Chemically modified siRNA: tools and applications. Drug Discov Today 2008;13(19-20):842–55.PubMedGoogle Scholar
  3. 3.
    Eder PS, DeVine RJ, Dagle JM, Walder JA. Substrate specificity and kinetics of degradation of antisense oligonucleotides by a 3’ exonuclease in plasma. Antisense Res Dev 1991;1(2):141–51.PubMedGoogle Scholar
  4. 4.
    Haupenthal J, Baehr C, Kiermayer S, Zeuzem S, Piiper A. Inhibition of RNAse A family enzymes prevents degradation and loss of silencing activity of siRNAs in serum. Biochem Pharmacol 2006;71(5):702–10.PubMedGoogle Scholar
  5. 5.
    Haupenthal J, Baehr C, Zeuzem S, Piiper A. RNAse A-like enzymes in serum inhibit the anti-neoplastic activity of siRNA targeting polo-like kinase 1. Int J Cancer 2007;121(1):206–10.PubMedGoogle Scholar
  6. 6.
    Kennedy S, Wang D, Ruvkun G. A conserved siRNA-degrading RNase negatively regulates RNA interference in C. elegans. Nature 2004;427(6975):645–9.Google Scholar
  7. 7.
    Turner JJ, Jones SW, Moschos SA, Lindsay MA, Gait MJ. MALDI-TOF mass spectral analysis of siRNA degradation in serum confirms an RNAse A-like activity. Mol Biosyst 2007;3(1):43–50.PubMedGoogle Scholar
  8. 8.
    Alexopoulou L, Holt AC, Medzhitov R, Flavell RA. Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature 2001;413(6857):732–8.PubMedGoogle Scholar
  9. 9.
    Diebold SS, Kaisho T, Hemmi H, Akira S, Reis e Sousa C. Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science 2004;303(5663):1529–31.Google Scholar
  10. 10.
    Stark GR, Kerr IM, Williams BR, Silverman RH, Schreiber RD. How cells respond to interferons. Annu Rev Biochem 1998;67:227–64.PubMedGoogle Scholar
  11. 11.
    Yoneyama M, Kikuchi M, Natsukawa T, et al. The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. Nat Immunol 2004;5(7):730–7.PubMedGoogle Scholar
  12. 12.
    Hornung V, Guenthner-Biller M, Bourquin C, et al. Sequence-specific potent induction of IFN-alpha by short interfering RNA in plasmacytoid dendritic cells through TLR7. Nat Med 2005;11(3):263–70.PubMedGoogle Scholar
  13. 13.
    Judge AD, Sood V, Shaw JR, Fang D, McClintock K, MacLachlan I. Sequence-dependent stimulation of the mammalian innate immune response by synthetic siRNA. Nat Biotechnol 2005;23(4):457–62.PubMedGoogle Scholar
  14. 14.
    Marques JT, Devosse T, Wang D, et al. A structural basis for discriminating between self and nonself double-stranded RNAs in mammalian cells. Nat Biotechnol 2006;24(5):559–65.PubMedGoogle Scholar
  15. 15.
    Omi K, Tokunaga K, Hohjoh H. Long-lasting RNAi activity in mammalian neurons. FEBS Lett 2004;558(1-3):89–95.PubMedGoogle Scholar
  16. 16.
    Bramsen JB, Laursen MB, Damgaard CK, et al. Improved silencing properties using small internally segmented interfering RNAs. Nucleic Acids Res 2007;35(17):5886–97.PubMedGoogle Scholar
  17. 17.
    Allerson CR, Sioufi N, Jarres R, et al. Fully 2’-modified oligonucleotide duplexes with improved in vitro potency and stability compared to unmodified small interfering RNA. J Med Chem 2005;48(4):901–4.PubMedGoogle Scholar
  18. 18.
    Blidner RA, Hammer RP, Lopez MJ, Robinson SO, Monroe WT. Fully 2’-deoxy-2’-fluoro substituted nucleic acids induce RNA interference in mammalian cell culture. Chem Biol Drug Des 2007;70(2):113–22.PubMedGoogle Scholar
  19. 19.
    Choung S, Kim YJ, Kim S, Park HO, Choi YC. Chemical modification of siRNAs to improve serum stability without loss of efficacy. Biochem Biophys Res Commun 2006;342(3):919–27.PubMedGoogle Scholar
  20. 20.
    Morrissey DV, Blanchard K, Shaw L, et al. Activity of stabilized short interfering RNA in a mouse model of hepatitis B virus replication. Hepatology 2005;41(6):1349–56.PubMedGoogle Scholar
  21. 21.
    Boado RJ. Blood-brain barrier transport of non-viral gene and RNAi therapeutics. Pharm Res 2007;24(9):1772–87.PubMedGoogle Scholar
  22. 22.
    Pardridge WM. shRNA and siRNA delivery to the brain. Adv Drug Deliv Rev 2007;59(2–3):141–52.PubMedGoogle Scholar
  23. 23.
    Whitehead KA, Langer R, Anderson DG. Knocking down barriers: advances in siRNA delivery. Nat Rev Drug Discov 2009;8(2):129–38.PubMedGoogle Scholar
  24. 24.
    Bartlett DW, Davis ME. Insights into the kinetics of siRNA-mediated gene silencing from live-cell and live-animal bioluminescent imaging. Nucleic Acids Res 2006;34(1):322–33.PubMedGoogle Scholar
  25. 25.
    Bogdanov AA, Jr. Merging molecular imaging and RNA interference: early experience in live animals. J Cell Biochem 2008;104(4):1113–23.PubMedGoogle Scholar
  26. 26.
    Braasch DA, Paroo Z, Constantinescu A, et al. Biodistribution of phosphodiester and phosphorothioate siRNA. Bioorg Med Chem Lett 2004;14(5):1139–43.PubMedGoogle Scholar
  27. 27.
    Chiu YL, Rana TM. RNAi in human cells: basic structural and functional features of small interfering RNA. Mol Cell 2002;10(3):549–61.PubMedGoogle Scholar
  28. 28.
    Zhang Y, Zhang YF, Bryant J, Charles A, Boado RJ, Pardridge WM. Intravenous RNA interference gene therapy targeting the human epidermal growth factor receptor prolongs survival in intracranial brain cancer. Clin Cancer Res 2004;10(11):3667–77.PubMedGoogle Scholar
  29. 29.
    Zhang Y, Schlachetzki F, Pardridge WM. Global non-viral gene transfer to the primate brain following intravenous administration. Mol Ther 2003;7(1):11–8.PubMedGoogle Scholar
  30. 30.
    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 2004;15(4):339–50.PubMedGoogle Scholar
  31. 31.
    Zhu C, Zhang Y, Zhang YF, Yi Li J, Boado RJ, Pardridge WM. Organ-specific expression of the lacZ gene controlled by the opsin promoter after intravenous gene administration in adult mice. J Gene Med 2004;6(8):906–12.Google Scholar
  32. 32.
    Torchilin VP. Recent advances with liposomes as pharmaceutical carriers. Nat Rev Drug Discov 2005;4(2):145–60.PubMedGoogle Scholar
  33. 33.
    Auguste DT, Furman K, Wong A, et al. Triggered release of siRNA from poly(ethylene glycol)-protected, pH-dependent liposomes. J Control Release 2008;130(3):266–74.PubMedGoogle Scholar
  34. 34.
    Rappaport J, Hanss B, Kopp JB, et al. Transport of phosphorothioate oligonucleotides in kidney: implications for molecular therapy. Kidney Int 1995;47(5):1462–9.PubMedGoogle Scholar
  35. 35.
    Mao S, Neu M, Germershaus O, et al. Influence of polyethylene glycol chain length on the physicochemical and biological properties of poly(ethylene imine)-graft-poly(ethylene glycol) block copolymer/SiRNA polyplexes. Bioconjug Chem 2006;17(5):1209–18.PubMedGoogle Scholar
  36. 36.
    Li W, Huang Z, MacKay JA, Grube S, Szoka FC, Jr. Low-pH-sensitive poly(ethylene glycol) (PEG)-stabilized plasmid nanolipoparticles: effects of PEG chain length, lipid composition and assembly conditions on gene delivery. J Gene Med 2005;7(1):67–79.PubMedGoogle Scholar
  37. 37.
    Akhtar S, Benter I. Toxicogenomics of non-viral drug delivery systems for RNAi: potential impact on siRNA-mediated gene silencing activity and specificity. Adv Drug Deliv Rev 2007;59(2-3):164–82.PubMedGoogle Scholar
  38. 38.
    Akhtar S, Benter IF. Nonviral delivery of synthetic siRNAs in vivo. J Clin Invest 2007;117(12):3623–32.PubMedGoogle Scholar
  39. 39.
    Lv H, Zhang S, Wang B, Cui S, Yan J. Toxicity of cationic lipids and cationic polymers in gene delivery. J Control Release 2006;114(1):100–9.PubMedGoogle Scholar
  40. 40.
    Ma Z, Li J, He F, Wilson A, Pitt B, Li S. Cationic lipids enhance siRNA-mediated interferon response in mice. Biochem Biophys Res Commun 2005;330(3):755–9.PubMedGoogle Scholar
  41. 41.
    Rust DM, Jameson G. The novel lipid delivery system of amphotericin B: drug profile and relevance to clinical practice. Oncol Nurs Forum 1998;25(1):35–48.PubMedGoogle Scholar
  42. 42.
    Akinc A, Zumbuehl A, Goldberg M, et al. A combinatorial library of lipid-like materials for delivery of RNAi therapeutics. Nat Biotechnol 2008;26(5):561–9.PubMedGoogle Scholar
  43. 43.
    Huang R, Ke W, Liu Y, Jiang C, Pei Y. The use of lactoferrin as a ligand for targeting the polyamidoamine-based gene delivery system to the brain. Biomaterials 2008;29(2):238–46.PubMedGoogle Scholar
  44. 44.
    Lungwitz U, Breunig M, Blunk T, Gopferich A. Polyethylenimine-based non-viral gene delivery systems. Eur J Pharm Biopharm 2005;60(2):247–66.PubMedGoogle Scholar
  45. 45.
    Tan PH, Yang LC, Shih HC, Lan KC, Cheng JT. Gene knockdown with intrathecal siRNA of NMDA receptor NR2B subunit reduces formalin-induced nociception in the rat. Gene Ther 2005;12(1):59–66.PubMedGoogle Scholar
  46. 46.
    Zintchenko A, Philipp A, Dehshahri A, Wagner E. Simple modifications of branched PEI lead to highly efficient siRNA carriers with low toxicity. Bioconjug Chem 2008;19(7):1448–55.PubMedGoogle Scholar
  47. 47.
    Heidel JD, Yu Z, Liu JY, et al. Administration in non-human primates of escalating intravenous doses of targeted nanoparticles containing ribonucleotide reductase subunit M2 siRNA. Proc Natl Acad Sci USA 2007;104(14):5715–21.PubMedGoogle Scholar
  48. 48.
    Pardridge WM. Brain drug targeting and gene technologies. Jpn J Pharmacol 2001;87(2):97–103.PubMedGoogle Scholar
  49. 49.
    Zhang Y, Pardridge WM. Rapid transferrin efflux from brain to blood across the blood-brain barrier. J Neurochem 2001;76(5):1597–600.PubMedGoogle Scholar
  50. 50.
    Pardridge WM. Blood-brain barrier drug targeting: the future of brain drug development. Mol Interv 2003;3(2):90–105, 51.Google Scholar
  51. 51.
    Giering JC, Grimm D, Storm TA, Kay MA. Expression of shRNA from a tissue-specific pol II promoter is an effective and safe RNAi therapeutic. Mol Ther 2008;16(9):1630–6.PubMedGoogle Scholar
  52. 52.
    Rao MK, Wilkinson MF. Tissue-specific and cell type-specific RNA interference in vivo. Nat Protoc 2006;1(3):1494–501.PubMedGoogle Scholar
  53. 53.
    Boado RJ, Zhang Y, Zhang Y, Pardridge WM. Humanization of anti-human insulin receptor antibody for drug targeting across the human blood-brain barrier. Biotechnol Bioeng 2007;96(2):381–91.PubMedGoogle Scholar
  54. 54.
    Coloma MJ, Lee HJ, Kurihara A, et al. Transport across the primate blood-brain barrier of a genetically engineered chimeric monoclonal antibody to the human insulin receptor. Pharm Res 2000;17(3):266–74.PubMedGoogle Scholar
  55. 55.
    Paskowitz DM, Greenberg KP, Yasumura D, et al. Rapid and stable knockdown of an endogenous gene in retinal pigment epithelium. Hum Gene Ther 2007;18(10):871–80.PubMedGoogle Scholar
  56. 56.
    Karmali PP, Chaudhuri A. Cationic liposomes as non-viral carriers of gene medicines: resolved issues, open questions, and future promises. Med Res Rev 2007;27(5):696–722.PubMedGoogle Scholar
  57. 57.
    Snyder RO, Flotte TR. Production of clinical-grade recombinant adeno-associated virus vectors. Curr Opin Biotechnol 2002;13(5):418–23.PubMedGoogle Scholar
  58. 58.
    Follenzi A, Santambrogio L, Annoni A. Immune responses to lentiviral vectors. Curr Gene Ther 2007;7(5):306–15.PubMedGoogle Scholar
  59. 59.
    Lowenstein PR, Mandel RJ, Xiong WD, Kroeger K, Castro MG. Immune responses to adenovirus and adeno-associated vectors used for gene therapy of brain diseases: the role of immunological synapses in understanding the cell biology of neuroimmune interactions. Curr Gene Ther 2007;7(5):347–60.PubMedGoogle Scholar
  60. 60.
    Zaldumbide A, Hoeben RC. How not to be seen: immune-evasion strategies in gene therapy. Gene Ther 2008;15(4):239–46.PubMedGoogle Scholar
  61. 61.
    Berkner KL. Development of adenovirus vectors for the expression of heterologous genes. Biotechniques 1988;6(7):616–29.PubMedGoogle Scholar
  62. 62.
    Fields BN KD, Howley PM, Chanock RM, Melnick JL, Monath TP, Roizman B, Straus SE Fields Virology. Third ed. Philadelphia, PA: Lippincott-Raven; 1996.Google Scholar
  63. 63.
    Kovesdi I, Brough DE, Bruder JT, Wickham TJ. Adenoviral vectors for gene transfer. Curr Opin Biotechnol 1997;8(5):583–9.PubMedGoogle Scholar
  64. 64.
    Douglas JT. Adenoviral vectors for gene therapy. Mol Biotechnol 2007;36(1):71–80.PubMedGoogle Scholar
  65. 65.
    Yang Y, Nunes FA, Berencsi K, Furth EE, Gonczol E, Wilson JM. Cellular immunity to viral antigens limits E1-deleted adenoviruses for gene therapy. Proc Natl Acad Sci U S A 1994;91(10):4407–11.PubMedGoogle Scholar
  66. 66.
    Alba R, Bosch A, Chillon M. Gutless adenovirus: last-generation adenovirus for gene therapy. Gene Ther 2005;12 Suppl 1:S18–27.PubMedGoogle Scholar
  67. 67.
    Davidson BL, Allen ED, Kozarsky KF, Wilson JM, Roessler BJ. A model system for in vivo gene transfer into the central nervous system using an adenoviral vector. Nat Genet 1993;3(3):219–23.PubMedGoogle Scholar
  68. 68.
    Kuo H, Ingram DK, Crystal RG, Mastrangeli A. Retrograde transfer of replication deficient recombinant adenovirus vector in the central nervous system for tracing studies. Brain Res 1995;705(1-2):31–8.PubMedGoogle Scholar
  69. 69.
    Le Gal La Salle G, Robert JJ, Berrard S, et al. An adenovirus vector for gene transfer into neurons and glia in the brain. Science 1993;259(5097):988–90.Google Scholar
  70. 70.
    Terashima T, Miwa A, Kanegae Y, Saito I, Okado H. Retrograde and anterograde labeling of cerebellar afferent projection by the injection of recombinant adenoviral vectors into the mouse cerebellar cortex. Anat Embryol (Berl) 1997;196(5):363–82.Google Scholar
  71. 71.
    Ilan Y, Saito H, Thummala NR, Chowdhury NR. Adenovirus-mediated gene therapy of liver diseases. Semin Liver Dis 1999;19(1):49–59.PubMedGoogle Scholar
  72. 72.
    Kamata Y, Tanabe A, Kanaji A, et al. Long-term normalization in the central nervous system, ocular manifestations, and skeletal deformities by a single systemic adenovirus injection into neonatal mice with mucopolysaccharidosis VII. Gene Ther 2003;10(5):406–14.PubMedGoogle Scholar
  73. 73.
    Berns KI. Parvovirus replication. Microbiol Rev 1990;54(3):316–29.PubMedGoogle Scholar
  74. 74.
    Carter BJ. Adeno-associated virus and the development of adeno-associated virus vectors: a historical perspective. Mol Ther 2004;10(6):981–9.PubMedGoogle Scholar
  75. 75.
    McCarty DM. Self-complementary AAV vectors; advances and applications. Mol Ther 2008;16(10):1648–56.PubMedGoogle Scholar
  76. 76.
    Afione SA, Wang J, Walsh S, Guggino WB, Flotte TR. Delayed expression of adeno-associated virus vector DNA. Intervirology 1999;42(4):213–20.PubMedGoogle Scholar
  77. 77.
    Song S, Embury J, Laipis PJ, Berns KI, Crawford JM, Flotte TR. Stable therapeutic serum levels of human alpha-1 antitrypsin (AAT) after portal vein injection of recombinant adeno-associated virus (rAAV) vectors. Gene Ther 2001;8(17):1299–306.PubMedGoogle Scholar
  78. 78.
    Song S, Morgan M, Ellis T, et al. Sustained secretion of human alpha-1-antitrypsin from murine muscle transduced with adeno-associated virus vectors. Proc Natl Acad Sci U S A 1998;95(24):14384–8.PubMedGoogle Scholar
  79. 79.
    Acland GM, Aguirre GD, Bennett J, et al. Long-term restoration of rod and cone vision by single dose rAAV-mediated gene transfer to the retina in a canine model of childhood blindness. Mol Ther 2005;12(6):1072–82.PubMedGoogle Scholar
  80. 80.
    Wu J, Zhao W, Zhong L, et al. Self-complementary recombinant adeno-associated viral vectors: packaging capacity and the role of rep proteins in vector purity. Hum Gene Ther 2007;18(2):171–82.PubMedGoogle Scholar
  81. 81.
    Gao G, Vandenberghe LH, Wilson JM. New recombinant serotypes of AAV vectors. Curr Gene Ther 2005;5(3):285–97.PubMedGoogle Scholar
  82. 82.
    Taymans JM, Vandenberghe LH, Haute CV, et al. Comparative analysis of adeno-associated viral vector serotypes 1, 2, 5, 7, and 8 in mouse brain. Hum Gene Ther 2007;18(3):195–206.PubMedGoogle Scholar
  83. 83.
    Liu G, Martins I, Wemmie JA, Chiorini JA, Davidson BL. Functional correction of CNS phenotypes in a lysosomal storage disease model using adeno-associated virus type 4 vectors. J Neurosci 2005;25(41):9321–7.PubMedGoogle Scholar
  84. 84.
    Foust KD, Nurre E, Montgomery CL, Hernandez A, Chan CM, Kaspar BK. Intravascular AAV9 preferentially targets neonatal neurons and adult astrocytes. Nat Biotechnol 2009;27(1):59–65.PubMedGoogle Scholar
  85. 85.
    McCown TJ. Adeno-associated virus (AAV) vectors in the CNS. Curr Gene Ther 2005;5(3):333–8.PubMedGoogle Scholar
  86. 86.
    Kaspar BK, Erickson D, Schaffer D, Hinh L, Gage FH, Peterson DA. Targeted retrograde gene delivery for neuronal protection. Mol Ther 2002;5(1):50–6.PubMedGoogle Scholar
  87. 87.
    Kaspar BK, Llado J, Sherkat N, Rothstein JD, Gage FH. Retrograde viral delivery of IGF-1 prolongs survival in a mouse ALS model. Science 2003;301(5634):839–42.PubMedGoogle Scholar
  88. 88.
    Peden CS, Burger C, Muzyczka N, Mandel RJ. Circulating anti-wild-type adeno-associated virus type 2 (AAV2) antibodies inhibit recombinant AAV2 (rAAV2)-mediated, but not rAAV5-mediated, gene transfer in the brain. J Virol 2004;78(12):6344–59.PubMedGoogle Scholar
  89. 89.
    Peden CS, Manfredsson FP, Reimsnider SK, et al. Striatal Readministration of rAAV Vectors Reveals an Immune Response Against AAV2 Capsids That Can Be Circumvented. Mol Ther 2009;17(3):524–37.PubMedGoogle Scholar
  90. 90.
    Dull T, Zufferey R, Kelly M, et al. A third-generation lentivirus vector with a conditional packaging system. J Virol 1998;72(11):8463-71.PubMedGoogle Scholar
  91. 91.
    Naldini L, Blomer U, Gallay P, et al. In vivo gene delivery and stable transduction of nondividing cells by a lentiviral vector. Science 1996;272(5259):263–7.PubMedGoogle Scholar
  92. 92.
    Zufferey R, Dull T, Mandel RJ, et al. Self-inactivating lentivirus vector for safe and efficient in vivo gene delivery. J Virol 1998;72(12):9873–80.PubMedGoogle Scholar
  93. 93.
    Mitrophanous K, Yoon S, Rohll J, et al. Stable gene transfer to the nervous system using a non-primate lentiviral vector. Gene Ther 1999;6(11):1808–18.PubMedGoogle Scholar
  94. 94.
    Poeschla EM, Wong-Staal F, Looney DJ. Efficient transduction of nondividing human cells by feline immunodeficiency virus lentiviral vectors. Nat Med 1998;4(3):354–7.PubMedGoogle Scholar
  95. 95.
    Jakobsson J, Lundberg C. Lentiviral vectors for use in the central nervous system. Mol Ther 2006;13(3):484–93.PubMedGoogle Scholar
  96. 96.
    Jakobsson J, Ericson C, Jansson M, Bjork E, Lundberg C. Targeted transgene expression in rat brain using lentiviral vectors. J Neurosci Res 2003;73(6):876–85.PubMedGoogle Scholar
  97. 97.
    McIver SR, Lee CS, Lee JM, et al. Lentiviral transduction of murine oligodendrocytes in vivo. J Neurosci Res 2005;82(3):397–403.PubMedGoogle Scholar
  98. 98.
    Mazarakis ND, Azzouz M, Rohll JB, et al. Rabies virus glycoprotein pseudotyping of lentiviral vectors enables retrograde axonal transport and access to the nervous system after peripheral delivery. Hum Mol Genet 2001;10(19):2109–21.PubMedGoogle Scholar
  99. 99.
    Singer O, Verma IM. Applications of lentiviral vectors for shRNA delivery and transgenesis. Curr Gene Ther 2008;8(6):483–8.PubMedGoogle Scholar
  100. 100.
    Sinn PL, Sauter SL, McCray PB, Jr. Gene therapy progress and prospects: development of improved lentiviral and retroviral vectors--design, biosafety, and production. Gene Ther 2005;12(14):1089–98.PubMedGoogle Scholar
  101. 101.
    Philippe S, Sarkis C, Barkats M, et al. Lentiviral vectors with a defective integrase allow efficient and sustained transgene expression in vitro and in vivo. Proc Natl Acad Sci U S A 2006;103(47):17684–9.PubMedGoogle Scholar
  102. 102.
    Yanez-Munoz RJ, Balaggan KS, MacNeil A, et al. Effective gene therapy with nonintegrating lentiviral vectors. Nat Med 2006;12(3):348–53.PubMedGoogle Scholar
  103. 103.
    Abordo-Adesida E, Follenzi A, Barcia C, et al. Stability of lentiviral vector-mediated transgene expression in the brain in the presence of systemic antivector immune responses. Hum Gene Ther 2005;16(6):741–51.PubMedGoogle Scholar
  104. 104.
    Annoni A, Battaglia M, Follenzi A, et al. The immune response to lentiviral-delivered transgene is modulated in vivo by transgene-expressing antigen-presenting cells but not by CD4+CD25+ regulatory T cells. Blood 2007;110(6):1788–96.PubMedGoogle Scholar
  105. 105.
    Follenzi A, Battaglia M, Lombardo A, Annoni A, Roncarolo MG, Naldini L. Targeting lentiviral vector expression to hepatocytes limits transgene-specific immune response and establishes long-term expression of human antihemophilic factor IX in mice. Blood 2004;103(10):3700–9.PubMedGoogle Scholar
  106. 106.
    DiFiglia M, Sena-Esteves M, Chase K, et al. Therapeutic silencing of mutant huntingtin with siRNA attenuates striatal and cortical neuropathology and behavioral deficits. Proc Natl Acad Sci U S A 2007;104(43):17204–9.PubMedGoogle Scholar
  107. 107.
    Franich NR, Fitzsimons HL, Fong DM, Klugmann M, During MJ, Young D. AAV vector-mediated RNAi of mutant huntingtin expression is neuroprotective in a novel genetic rat model of Huntington’s disease. Mol Ther 2008;16(5):947–56.PubMedGoogle Scholar
  108. 108.
    Grimm D, Streetz KL, Jopling CL, et al. Fatality in mice due to oversaturation of cellular microRNA/short hairpin RNA pathways. Nature 2006;441(7092):537–41.PubMedGoogle Scholar
  109. 109.
    McBride JL, Boudreau RL, Harper SQ, et al. Artificial miRNAs mitigate shRNA-mediated toxicity in the brain: implications for the therapeutic development of RNAi. Proc Natl Acad Sci U S A 2008;105(15):5868–73.PubMedGoogle Scholar
  110. 110.
    Levin BE, Becker TC, Eiki J, Zhang BB, Dunn-Meynell AA. Ventromedial hypothalamic glucokinase is an important mediator of the counterregulatory response to insulin-induced hypoglycemia. Diabetes 2008;57(5):1371–9.PubMedGoogle Scholar
  111. 111.
    Lin Z, Chen Y, Zhang W, Chen AF, Lin S, Morris M. RNA interference shows interactions between mouse brainstem angiotensin AT1 receptors and angiotensin-converting enzyme 2. Exp Physiol 2008;93(5):676–84.PubMedGoogle Scholar
  112. 112.
    White MD, Farmer M, Mirabile I, Brandner S, Collinge J, Mallucci GR. Single treatment with RNAi against prion protein rescues early neuronal dysfunction and prolongs survival in mice with prion disease. Proc Natl Acad Sci U S A 2008;105(29):10238–43.PubMedGoogle Scholar
  113. 113.
    Raoul C, Abbas-Terki T, Bensadoun JC, et al. Lentiviral-mediated silencing of SOD1 through RNA interference retards disease onset and progression in a mouse model of ALS. Nat Med 2005;11(4):423–8.PubMedGoogle Scholar
  114. 114.
    Yoo JY, Kim JH, Kim J, et al. Short hairpin RNA-expressing oncolytic adenovirus-mediated inhibition of IL-8: effects on antiangiogenesis and tumor growth inhibition. Gene Ther 2008;15(9):635–51.PubMedGoogle Scholar
  115. 115.
    Yoo JY, Kim JH, Kwon YG, et al. VEGF-specific short hairpin RNA-expressing oncolytic adenovirus elicits potent inhibition of angiogenesis and tumor growth. Mol Ther 2007;15(2):295–302.PubMedGoogle Scholar
  116. 116.
    Wang H, Ghosh A, Baigude H, et al. Therapeutic gene silencing delivered by a chemically modified small interfering RNA against mutant SOD1 slows amyotrophic lateral sclerosis progression. J Biol Chem 2008;283(23):15845–52.PubMedGoogle Scholar
  117. 117.
    Dore-Savard L, Roussy G, Dansereau MA, et al. Central delivery of Dicer-substrate siRNA: a direct application for pain research. Mol Ther 2008;16(7):1331–9.PubMedGoogle Scholar
  118. 118.
    Butti E, Bergami A, Recchia A, et al. Absence of an intrathecal immune reaction to a helper-dependent adenoviral vector delivered into the cerebrospinal fluid of non-human primates. Gene Ther 2008;15(3):233–8.PubMedGoogle Scholar
  119. 119.
    Watson G, Bastacky J, Belichenko P, et al. Intrathecal administration of AAV vectors for the treatment of lysosomal storage in the brains of MPS I mice. Gene Ther 2006;13(11):917–25.PubMedGoogle Scholar
  120. 120.
    Fedorova E, Battini L, Prakash-Cheng A, Marras D, Gusella GL. Lentiviral gene delivery to CNS by spinal intrathecal administration to neonatal mice. J Gene Med 2006;8(4):414–24.PubMedGoogle Scholar
  121. 121.
    Miller TM, Kaspar BK, Kops GJ, et al. Virus-delivered small RNA silencing sustains strength in amyotrophic lateral sclerosis. Ann Neurol 2005;57(5):773–6.PubMedGoogle Scholar
  122. 122.
    Miller TM, Kim SH, Yamanaka K, et al. Gene transfer demonstrates that muscle is not a ­primary target for non-cell-autonomous ­toxicity in familial amyotrophic lateral ­sclerosis. Proc Natl Acad Sci U S A 2006;103(51):19546–51.PubMedGoogle Scholar
  123. 123.
    Ralph GS, Radcliffe PA, Day DM, et al. Silencing mutant SOD1 using RNAi protects against neurodegeneration and extends ­survival in an ALS model. Nat Med 2005;11(4):429–33.PubMedGoogle Scholar
  124. 124.
    Martinov VN, Sefland I, Walaas SI, Lomo T, Nja A, Hoover F. Targeting functional subtypes of spinal motoneurons and skeletal muscle fibers in vivo by intramuscular injection of adenoviral and adeno-associated viral vectors. Anat Embryol (Berl) 2002;205(3):215–21.Google Scholar
  125. 125.
    Nakajima H, Uchida K, Kobayashi S, et al. Target muscles for retrograde gene delivery to specific spinal cord segments. Neurosci Lett 2008;435(1):1–6.PubMedGoogle Scholar
  126. 126.
    Yamashita S, Mita S, Kato S, Okado H, Ohama E, Uchino M. Effect on motor ­neuron survival in mutant SOD1 (G93A) transgenic mice by Bcl-2 expression using retrograde axonal transport of adenoviral ­vectors. Neurosci Lett 2002;328(3):289–93.PubMedGoogle Scholar
  127. 127.
    Pardridge WM. Drug and gene targeting to the brain with molecular Trojan horses. Nat Rev Drug Discov 2002;1(2):131–9.PubMedGoogle Scholar
  128. 128.
    Xia CF, Zhang Y, Zhang Y, Boado RJ, Pardridge WM. Intravenous siRNA of brain cancer with receptor targeting and avidin-biotin tech­­nology. Pharm Res 2007;24(12):2309–16.PubMedGoogle Scholar
  129. 129.
    Kumar P, Wu H, McBride JL, et al. Transvascular delivery of small interfering RNA to the central nervous system. Nature 2007;448(7149):39–43.PubMedGoogle Scholar
  130. 130.
    Lowenstein PR. Crossing the rubicon. Nat Biotechnol 2009;27(1):42–4.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.The Research Institute at Nationwide Children’s HospitalColumbusUSA
  2. 2.Department of PediatricsThe Ohio State UniversityColumbusUSA

Personalised recommendations