Neurotherapeutics

, Volume 11, Issue 4, pp 817–839 | Cite as

Gene Therapy for the Nervous System: Challenges and New Strategies

  • Casey A. Maguire
  • Servio H. Ramirez
  • Steven F. Merkel
  • Miguel Sena-Esteves
  • Xandra O. Breakefield
Review

Abstract

Current clinical treatments for central nervous system (CNS) diseases, such as Parkinson’s disease and glioblastoma do not halt disease progression and have significant treatment morbidities. Gene therapy has the potential to “permanently” correct disease by bringing in a normal gene to correct a mutant gene deficiency, knocking down mRNA of mutant alleles, and inducing cell-death in cancer cells using transgenes encoding apoptosis-inducing proteins. Promising results in clinical trials of eye disease (Leber’s congenital aumorosis) and Parkinson’s disease have shown that gene-based neurotherapeutics have great potential. The recent development of genome editing technology, such as zinc finger nucleases, TALENS, and CRISPR, has made the ultimate goal of gene correction a step closer. This review summarizes the challenges faced by gene-based neurotherapeutics and the current and recent strategies designed to overcome these barriers. We have chosen the following challenges to focus on in this review: (1) delivery vehicles (both virus and nonviral), (2) use of promoters for vector-mediated gene expression in CNS, and (3) delivery across the blood-brain barrier. The final section (4) focuses on promising pre-clinical/clinical studies of neurotherapeutics.

Keywords

Gene delivery Central nervous system Virus vector Nonviral gene delivery Gene therapy 

Notes

Acknowledgments

We thank Ms. Suzanne McDavitt for skilled editorial assistance, Ms. Emily Mills at Millstone Design for preparation of figures and Dr. Thurman Wheeler for scientific insights. This work was supported by National Institutes of Health/National Cancer Institute (NIH/NCI) U19 CA179563, which is supported by the NIH Common Fund, through the Office of Strategic Coordination/Office of the NIH Director and CA069246 and Voices Against Brain Cancer (XOB). The work performed in the authors’ laboratory is supported by grants from a National Institute on Drug Abuse (NIDA) training grant: T32 DA007237 (S.M.), NIH/National Institute of Neurological Disorders and Stroke (NINDS) R01 NS086570-01 (S.H.R.) and The Shriners Hospitals for Children 85110-PHI-14 (S.H.R.). C.M. is supported by an NIH/NINDS R21 NS081374-01. C.M. has a financial interest in Exosome Diagnostics, Inc. C.M.’s interests were reviewed and are managed by the Massachusetts General Hospital and Partners HealthCare in accordance with their conflict of interest policies. C.M. has filed patent applications related to the vexosome technology.

Required Author Forms

Disclosure forms provided by the authors are available with the online version of this article.

Supplementary material

13311_2014_299_MOESM1_ESM.pdf (1.2 mb)
ESM 1(PDF 1225 kb)

References

  1. 1.
    Simonato M, Bennett J, Boulis NM, et al. Progress in gene therapy for neurological disorders. Nat Rev Neurol 2013;9:277–291.PubMedPubMedCentralGoogle Scholar
  2. 2.
    Nagabhushan Kalburgi S, Khan NN, Gray SJ. Recent gene therapy advancements for neurological diseases. Discov Med 2013;15:111–119.PubMedGoogle Scholar
  3. 3.
    Lo WD, Qu G, Sferra TJ, et al. Adeno-associated virus-mediated gene transfer to the brain: duration and modulation of expression. Hum Gene Ther 1999;10:201–213.PubMedGoogle Scholar
  4. 4.
    Puntel M, Kroeger KM, Sanderson NS, et al. Gene transfer into rat brain using adenoviral vectors. Curr Protoc Neurosci Chapter 4:Unit 4.24.Google Scholar
  5. 5.
    Deroose CM, Reumers V, Gijsbers R, et al. Noninvasive monitoring of long-term lentiviral vector-mediated gene expression in rodent brain with bioluminescence imaging. Mol Ther 2006;14:423–431.PubMedGoogle Scholar
  6. 6.
    Zeier Z, Aguilar JS, Lopez CM et al. A limited innate immune response is induced by a replication-defective herpes simplex virus vector following delivery to the murine central nervous system. J Neurovirol 2009;15:411–424.PubMedPubMedCentralGoogle Scholar
  7. 7.
    Kuriyama N, Kuriyama H, Julin CM, Lamborn K, Israel MA. Pretreatment with protease is a useful experimental strategy for enhancing adenovirus-mediated cancer gene therapy. Hum Gene Ther 2000;11:2219–2230.PubMedGoogle Scholar
  8. 8.
    Maillard L, Ziol M, Tahlil O, et al. Pre-treatment with elastase improves the efficiency of percutaneous adenovirus-mediated gene transfer to the arterial media. Gene Ther 1998;5:1023–1030.PubMedGoogle Scholar
  9. 9.
    Favre D, Cherel Y, Provost N, et al. Hyaluronidase enhances recombinant adeno-associated virus (rAAV)-mediated gene transfer in the rat skeletal muscle. Gene Ther 2000;7:1417–1420.PubMedGoogle Scholar
  10. 10.
    Hadaczek P, Mirek H, Bringas J, Cunningham J, Bankiewicz K. Basic fibroblast growth factor enhances transduction, distribution, and axonal transport of adeno-associated virus type 2 vector in rat brain. Hum Gene Ther 2004;15:469–479.PubMedGoogle Scholar
  11. 11.
    Mocanu JD, Yip KW, Alajez NM, et al. Imaging the modulation of adenoviral kinetics and biodistribution for cancer gene therapy. Mol Ther 2007;15:921–929.PubMedGoogle Scholar
  12. 12.
    White E, Bienemann A, Megraw L, et al. Distribution properties of lentiviral vectors administered into the striatum by convection-enhanced delivery. Hum Gene Ther 2012;23:115–127.PubMedGoogle Scholar
  13. 13.
    Hadaczek P, Kohutnicka M, Krauze MT, et al. Convection-enhanced delivery of adeno-associated virus type 2 (AAV2) into the striatum and transport of AAV2 within monkey brain. Hum Gene Ther 2006;17:291–302.PubMedGoogle Scholar
  14. 14.
    Kells AP, Hadaczek P, Yin D, et al. Efficient gene therapy-based method for the delivery of therapeutics to primate cortex. Proc Natl Acad Sci USA 2009;106:2407–2411.PubMedPubMedCentralGoogle Scholar
  15. 15.
    Cearley CN, Wolfe JH. A single injection of an adeno-associated virus vector into nuclei with divergent connections results in widespread vector distribution in the brain and global correction of a neurogenetic disease. J Neurosci 2007;27:9928–9940.PubMedGoogle Scholar
  16. 16.
    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;18:195–206.PubMedGoogle Scholar
  17. 17.
    Meijer DH, Maguire CA, LeRoy SG, Sena-Esteves M. Controlling brain tumor growth by intraventricular administration of an AAV vector encoding IFN-beta. Cancer Gene Ther 2009;16:664–671.PubMedPubMedCentralGoogle Scholar
  18. 18.
    Samaranch L, Salegio EA, San Sebastian W, et al. Strong cortical and spinal cord transduction after AAV7 and AAV9 delivery into the cerebrospinal fluid of nonhuman primates. Hum Gene Ther 2013;24:526–532.PubMedPubMedCentralGoogle Scholar
  19. 19.
    Chang M, Cooper JD, Sleat DE, et al. Intraventricular enzyme replacement improves disease phenotypes in a mouse model of late infantile neuronal ceroid lipofuscinosis. Mol Ther 2008;16:649–656.PubMedGoogle Scholar
  20. 20.
    Zhuang X, Xiang X, Grizzle W, et al. Treatment of brain inflammatory diseases by delivering exosome encapsulated anti-inflammatory drugs from the nasal region to the brain. Mol Ther 2011;19:1769–1779.PubMedPubMedCentralGoogle Scholar
  21. 21.
    Foust KD, Nurre E, Montgomery CL, et al. Intravascular AAV9 preferentially targets neonatal neurons and adult astrocytes. Nat Biotechnol 2009;27:59–65.PubMedPubMedCentralGoogle Scholar
  22. 22.
    Pardridge WM. The blood-brain barrier: bottleneck in brain drug development. NeuroRx 2005;2:3–14.PubMedPubMedCentralGoogle Scholar
  23. 23.
    Peng KW, Pham L, Ye H, et al. Organ distribution of gene expression after intravenous infusion of targeted and untargeted lentiviral vectors. Gene Ther 2001;8:1456–1463.PubMedGoogle Scholar
  24. 24.
    Tao N, Gao GP, Parr M, et al. Sequestration of adenoviral vector by Kupffer cells leads to a nonlinear dose response of transduction in liver. Mol Ther 2001;3:28–35.PubMedGoogle Scholar
  25. 25.
    Zincarelli C, Soltys S, Rengo G, Rabinowitz JE. Analysis of AAV serotypes 1–9 mediated gene expression and tropism in mice after systemic injection. Mol Ther 2008;16:1073–1080.PubMedGoogle Scholar
  26. 26.
    Ganesan LP, Mohanty S, Kim J, et al. Rapid and efficient clearance of blood-borne virus by liver sinusoidal endothelium. PLoS Pathog 2011;7:e1002281.PubMedPubMedCentralGoogle Scholar
  27. 27.
    Duale H, Kasparov S, Paton JF, Teschemacher AG. Differences in transductional tropism of adenoviral and lentiviral vectors in the rat brainstem. Exp Physiol 2005;90:71–78.PubMedGoogle Scholar
  28. 28.
    Berges BK, Wolfe JH, Fraser MW. Transduction of brain by herpes simplex virus vectors. Mol Ther 2007;15:20–29.PubMedGoogle Scholar
  29. 29.
    Piccolo P, Vetrini F, Mithbaokar P, et al. SR-A and SREC-I are Kupffer and endothelial cell receptors for helper-dependent adenoviral vectors. Mol Ther 2013;21:767–774.PubMedPubMedCentralGoogle Scholar
  30. 30.
    Pien GC, Basner-Tschakarjan E, Hui DJ, et al. Capsid antigen presentation flags human hepatocytes for destruction after transduction by adeno-associated viral vectors. J Clin Invest 2009;119:1688–95.PubMedPubMedCentralGoogle Scholar
  31. 31.
    Siders WM, Shields J, Kaplan J, et al. Cytotoxic T lymphocyte responses to transgene product, not adeno-associated viral capsid protein, limit transgene expression in mice. Hum Gene Ther 2009;20:11–20.PubMedPubMedCentralGoogle Scholar
  32. 32.
    Tian J, Xu Z, Smith JS, et al. Adenovirus activates complement by distinctly different mechanisms in vitro and in vivo: indirect complement activation by virions in vivo. J Virol 2009;83:5648–5658.PubMedPubMedCentralGoogle Scholar
  33. 33.
    Scallan CD, Jiang H, Liu T, et al. Human immunoglobulin inhibits liver transduction by AAV vectors at low AAV2 neutralizing titers in SCID mice. Blood 2006;107:1810–1817.PubMedGoogle Scholar
  34. 34.
    Basner-Tschakarjan E, Bijjiga E, Martino AT. Pre-clinical assessment of immune responses to adeno-associated virus (AAV) vectors. Front Immunol 2014;5:28.PubMedPubMedCentralGoogle Scholar
  35. 35.
    Treleaven CM, Tamsett TJ, Bu J, et al. Gene transfer to the CNS is efficacious in immune-primed mice harboring physiologically relevant titers of anti-AAV antibodies. Mol Ther 2012;20:1713–1723.PubMedPubMedCentralGoogle Scholar
  36. 36.
    Gray SJ, Nagabhushan Kalburgi S, McCown TJ, Jude Samulski R. Global CNS gene delivery and evasion of anti-AAV-neutralizing antibodies by intrathecal AAV administration in non-human primates. Gene Ther 2013;20:450–459.PubMedPubMedCentralGoogle Scholar
  37. 37.
    Thomas CE, Birkett D, Anozie I, Castro MG, Lowenstein PR. Acute direct adenoviral vector cytotoxicity and chronic, but not acute, inflammatory responses correlate with decreased vector-mediated transgene expression in the brain. Mol Ther 2001;3:36–46.PubMedGoogle Scholar
  38. 38.
    Ciesielska, A., P. Hadaczek, G. Mittermeyer, et al., Cerebral infusion of AAV9 vector-encoding non-self proteins can elicit cell-mediated immune responses. Mol Ther. 21: p. 158–66.Google Scholar
  39. 39.
    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;12:1072–1082.PubMedPubMedCentralGoogle Scholar
  40. 40.
    Acland GM, Aguirre GD, Ray J, et al. Gene therapy restores vision in a canine model of childhood blindness. Nat Genet 2001;28:92–95.PubMedGoogle Scholar
  41. 41.
    Simonelli F, Maguire AM, Testa F, et al. Gene therapy for Leber’s congenital amaurosis is safe and effective through 1.5 years after vector administration. Mol Ther 2010;18:643–650.PubMedPubMedCentralGoogle Scholar
  42. 42.
    Maguire AM, High KA, Auricchio A, et al. Age-dependent effects of RPE65 gene therapy for Leber’s congenital amaurosis: a phase 1 dose-escalation trial. Lancet 2009;374:1597–1605.PubMedGoogle Scholar
  43. 43.
    Hacein-Bey-Abina S, Garrigue A, Wang GP, et al. Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1. J Clin Invest 2008;118:3132–3142.PubMedPubMedCentralGoogle Scholar
  44. 44.
    Raper SE, Chirmule N, Lee FS, et al. Fatal systemic inflammatory response syndrome in a ornithine transcarbamylase deficient patient following adenoviral gene transfer. Mol Genet Metab 2003;80:148–158.PubMedGoogle Scholar
  45. 45.
    Ylä-Herttuala S. Endgame: glybera finally recommended for approval as the first gene therapy drug in the European union. Mol Ther 2012;20:1831–1832.PubMedPubMedCentralGoogle Scholar
  46. 46.
    Rogers ML, Rush RA. Non-viral gene therapy for neurological diseases, with an emphasis on targeted gene delivery. J Control Release 2012;157:183–189.PubMedGoogle Scholar
  47. 47.
    Samaranch L, Salegio EA, San Sebastian W, et al. Adeno-associated virus serotype 9 transduction in the central nervous system of nonhuman primates. Hum Gene Ther 2012;23:382–389.PubMedPubMedCentralGoogle Scholar
  48. 48.
    Gray SJ, Matagne V, Bachaboina L, et al. Preclinical differences of intravascular AAV9 delivery to neurons and glia: a comparative study of adult mice and nonhuman primates. Mol Ther 2011;19:1058–1069.PubMedPubMedCentralGoogle Scholar
  49. 49.
    Zhang H, Yang B, Mu X, et al. Several rAAV vectors efficiently cross the blood-brain barrier and transduce neurons and astrocytes in the neonatal mouse central nervous system. Mol Ther 2011;19:1440–1448.PubMedPubMedCentralGoogle Scholar
  50. 50.
    Louboutin JP, Chekmasova AA, Marusich E, Chowdhury JR, Strayer DS. Efficient CNS gene delivery by intravenous injection. Nat Methods 2010;7:905–907.PubMedGoogle Scholar
  51. 51.
    Wollmann G, Ozduman K, van den Pol AN. Oncolytic virus therapy for glioblastoma multiforme: concepts and candidates. Cancer J 2012;18:69–81.PubMedPubMedCentralGoogle Scholar
  52. 52.
    Fueyo J, Alemany R, Gomez-Manzano V, et al. Preclinical characterization of the antiglioma activity of a tropism-enhanced adenovirus targeted to the retinoblastoma pathway. J Natl Cancer Inst 2003;95:652–660.PubMedGoogle Scholar
  53. 53.
    Nakamura T, Peng KW, Harvey M, et al. Rescue and propagation of fully retargeted oncolytic measles viruses. Nat Biotechnol 2005;23:209–214.PubMedGoogle Scholar
  54. 54.
    Ostertag D, Amundson KK, Lopez Espinoza F, et al. Brain tumor eradication and prolonged survival from intratumoral conversion of 5-fluorocytosine to 5-fluorouracil using a nonlytic retroviral replicating vector. Neuro Oncol 14:145–159.Google Scholar
  55. 55.
    Stemmer WP. Rapid evolution of a protein in vitro by DNA shuffling. Nature 1994;370:389–391.PubMedGoogle Scholar
  56. 56.
    Li W, Asokan A, Wu Z, et al. Engineering and selection of shuffled AAV genomes: a new strategy for producing targeted biological nanoparticles. Mol Ther 2008;16:1252–1260.PubMedPubMedCentralGoogle Scholar
  57. 57.
    Grimm D, Lee JS, Wang L, et al. In vitro and in vivo gene therapy vector evolution via multispecies interbreeding and retargeting of adeno-associated viruses. J Virol 2008;82:5887–5911.PubMedPubMedCentralGoogle Scholar
  58. 58.
    Koerber JT, Jang JH, Schaffer DV. DNA shuffling of adeno-associated virus yields functionally diverse viral progeny. Mol Ther 2008;16:1703–1709.PubMedPubMedCentralGoogle Scholar
  59. 59.
    Powell SK, Kaloss MA, Pinkstaff A, et al. Breeding of retroviruses by DNA shuffling for improved stability and processing yields. Nat Biotechnol 2000;18:1279–1282.PubMedGoogle Scholar
  60. 60.
    Maguire CA, Gianni D, Meijer DH, et al. Directed evolution of adeno-associated virus for glioma cell transduction. J Neurooncol 2010;96:337–347.PubMedPubMedCentralGoogle Scholar
  61. 61.
    Gray SJ, Blake BL, Criswell HE, et al. Directed evolution of a novel adeno-associated virus (AAV) vector that crosses the seizure-compromised blood-brain barrier (BBB). Mol Ther 2010;18:570–578.PubMedPubMedCentralGoogle Scholar
  62. 62.
    Koerber JT, Klimczak R, Jang JH, et al. Molecular evolution of adeno-associated virus for enhanced glial gene delivery. Mol Ther 2009;17:2088–2095.PubMedPubMedCentralGoogle Scholar
  63. 63.
    Jang JH, Koerber JT, Kim JS, et al. An evolved adeno-associated viral variant enhances gene delivery and gene targeting in neural stem cells. Mol Ther 2011;19:667–675.PubMedPubMedCentralGoogle Scholar
  64. 64.
    Maheshri N, Koerber JT, Kaspar BK, Schaffer DV. Directed evolution of adeno-associated virus yields enhanced gene delivery vectors. Nat Biotechnol 2006;24:198–204.PubMedGoogle Scholar
  65. 65.
    Dassie JP, Giangrande PH. Current progress on aptamer-targeted oligonucleotide therapeutics. Ther Deliv 2013;4:1527–1546.PubMedPubMedCentralGoogle Scholar
  66. 66.
    Anliker B, Abel T, Kneissl S, et al. Specific gene transfer to neurons, endothelial cells and hematopoietic progenitors with lentiviral vectors. Nat Methods 2010;7:929–935.PubMedGoogle Scholar
  67. 67.
    Candolfi M, Xiong W, Yagiz K, et al. Gene therapy-mediated delivery of targeted cytotoxins for glioma therapeutics. Proc Natl Acad Sci USA 2010;107:20021–20026.PubMedPubMedCentralGoogle Scholar
  68. 68.
    Uchida H, Marzulli M, Nakano K, et al. Effective treatment of an orthotopic xenograft model of human glioblastoma using an EGFR-retargeted oncolytic herpes simplex virus. Mol Ther 2013;21:561–569.PubMedPubMedCentralGoogle Scholar
  69. 69.
    Maguire CA, Meijer DH, LeRoy SG, et al. Preventing growth of brain tumors by creating a zone of resistance. Mol Ther 2008;16:1695–1702.PubMedPubMedCentralGoogle Scholar
  70. 70.
    Kugler S, Kilic E, Bahr M. Human synapsin 1 gene promoter confers highly neuron-specific long-term transgene expression from an adenoviral vector in the adult rat brain depending on the transduced area. Gene Ther 2003;10:337–347.PubMedGoogle Scholar
  71. 71.
    Wang CY, Wang S. Astrocytic expression of transgene in the rat brain mediated by baculovirus vectors containing an astrocyte-specific promoter. Gene Ther 2006;13:1447–1456.PubMedGoogle Scholar
  72. 72.
    Semple-Rowland SL, Coggin WE, Geesey M, et al. Expression characteristics of dual-promoter lentiviral vectors targeting retinal photoreceptors and Muller cells. Mol Vis 2010;16:916–934.PubMedPubMedCentralGoogle Scholar
  73. 73.
    Gentner B, Visigalli I, Hiramatsu H, et al. Identification of hematopoietic stem cell-specific miRNAs enables gene therapy of globoid cell leukodystrophy. Sci Transl Med 2010;2:58–84.Google Scholar
  74. 74.
    Ahmed SS, Li H, Cao C, et al. A single intravenous rAAV injection as late as P20 achieves efficacious and sustained CNS gene therapy in canavan mice. Mol Ther 2013; 21:2136–2147.PubMedGoogle Scholar
  75. 75.
    Annoni A, Brown BD, Cantore A, et al. In vivo delivery of a microRNA-regulated transgene induces antigen-specific regulatory T cells and promotes immunologic tolerance. Blood 2009;114:1552–1561.Google Scholar
  76. 76.
    Muhammad AK, Xiong W, Puntel M, et al. Safety profile of gutless adenovirus vectors delivered into the normal brain parenchyma: implications for a glioma phase 1 clinical trial. Hum Gene Ther Methods 2012;23:271–284.PubMedGoogle Scholar
  77. 77.
    Rungta RL, Choi HB, Lin PJ, et al. Lipid nanoparticle delivery of siRNA to silence neuronal gene expression in the brain. Mol Ther Nucleic Acids 2013;2: e136.PubMedPubMedCentralGoogle Scholar
  78. 78.
    Regina A, Demeule M, Che C, et al. Antitumour activity of ANG1005, a conjugate between paclitaxel and the new brain delivery vector Angiopep-2. Br J Pharmacol 2008;155:185–197.PubMedPubMedCentralGoogle Scholar
  79. 79.
    Demeule M, Regina A, Che C, et al. Identification and design of peptides as a new drug delivery system for the brain. J Pharmacol Exp Ther 2008;324:1064–1072.PubMedGoogle Scholar
  80. 80.
    Huang R, Ma H, Guo Y, et al. Angiopep-conjugated nanoparticles for targeted long-term gene therapy of Parkinson’s disease. Pharm Res 2013;30:2549–2559.PubMedGoogle Scholar
  81. 81.
    Liu HL, Hua MY, Yang HW, et al. Magnetic resonance monitoring of focused ultrasound/magnetic nanoparticle targeting delivery of therapeutic agents to the brain. Proc Natl Acad Sci USA 2010;107:15205–15210.PubMedPubMedCentralGoogle Scholar
  82. 82.
    Huang, Q, Deng J, Xie Z, et al. Effective gene transfer into central nervous system following ultrasound-microbubbles-induced opening of the blood-brain barrier. Ultrasound Med Biol 2012;38:1234–1243.PubMedGoogle Scholar
  83. 83.
    van der Vos KE, Balaj L, Skog J, Breakefield XO. Brain tumor microvesicles: insights into intercellular communication in the nervous system. Cell Mol Neurobiol 2011;31:949–959.PubMedPubMedCentralGoogle Scholar
  84. 84.
    Alvarez-Erviti L, Seow Y, Yin H, et al. Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat Biotechnol 2011;29:341–345.PubMedGoogle Scholar
  85. 85.
    Kooijmans SA, Stremersch S, Braeckmans K, et al. Electroporation-induced siRNA precipitation obscures the efficiency of siRNA loading into extracellular vesicles. J Control Release 2013;172:229–238.PubMedGoogle Scholar
  86. 86.
    Gyorgy B, Fitzpatrick Z, Crommentuijn MH et al. Naturally enveloped AAV vectors for shielding neutralizing antibodies and robust gene delivery in vivo. Biomaterials 2014;35:7598–7560.PubMedGoogle Scholar
  87. 87.
    Skog J, Wurdinger T, van Rijn S, et al. Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat Cell Biol 2008;10:1470–1476.PubMedPubMedCentralGoogle Scholar
  88. 88.
    Villarroya-Beltri C, Gutierrez-Vazquez C, Sanchez-Cabo F, et al. Sumoylated hnRNPA2B1 controls the sorting of miRNAs into exosomes through binding to specific motifs. Nat Commun 2013;4:2980.PubMedPubMedCentralGoogle Scholar
  89. 89.
    Bolukbasi MF, Mizrak A, Ozdener GB, et al. miR-1289 and “zipcode”-like sequence enrich mRNAs in microvesicles. Mol Ther Nucleic Acids 2012;1:e10.PubMedPubMedCentralGoogle Scholar
  90. 90.
    Munoz JL, Bliss SA, Greco SJ, et al. Delivery of functional anti-miR-9 by mesenchymal stem cell-derived exosomes to glioblastoma multiforme cells conferred chemosensitivity. Mol Ther Nucleic Acids 2013;2:e126.PubMedPubMedCentralGoogle Scholar
  91. 91.
    Mooney R, Weng Y, Tirughana-Sambandan R, et al. Neural stem cells improve intracranial nanoparticle retention and tumor-selective distribution. Future Oncol 2014;10:401–415.PubMedGoogle Scholar
  92. 92.
    Rossignol J, Fink K, Davis K, et al. Transplants of adult mesenchymal and neural stem cells provide neuroprotection and behavioral sparing in a transgenic rat model of Huntington’s disease. Stem Cells 2014;32:500–509.PubMedGoogle Scholar
  93. 93.
    Hajitou A, Trepel M, Lilley CE, et al. A hybrid vector for ligand-directed tumor targeting and molecular imaging. Cell 2006;125:385–398.PubMedGoogle Scholar
  94. 94.
    Kia A, Przystal JM, Nianiaris N, et al. Dual systemic tumor targeting with ligand-directed phage and Grp78 promoter induces tumor regression. Mol Cancer Ther 2012;11:2566–2577.PubMedPubMedCentralGoogle Scholar
  95. 95.
    Maguire CA, Balaj L, Sivaraman S, et al. Microvesicle-associated AAV vector as a novel gene delivery system. Mol Ther 2012;20:960–971.PubMedPubMedCentralGoogle Scholar
  96. 96.
    Bevan AK, Duque S, Foust KD, et al. Systemic gene delivery in large species for targeting spinal cord, brain, and peripheral tissues for pediatric disorders. Mol Ther 2011;19:1971–1980.PubMedPubMedCentralGoogle Scholar
  97. 97.
    Yang B, Li S, Wang H, et al. Global CNS transduction of adult mice by intravenously delivered rAAVrh.8 and rAAVrh.10 and nonhuman primates by rAAVrh.10. Mol Ther 2014; 22:1299–1309.PubMedGoogle Scholar
  98. 98.
    Duque S, Joussemet B, Riviere C, et al. Intravenous administration of self-complementary AAV9 enables transgene delivery to adult motor neurons. Mol Ther 2009;17:1187–1196.PubMedPubMedCentralGoogle Scholar
  99. 99.
    Burger C, Gorbatyuk OS, Velardo MJ, et al. Recombinant AAV viral vectors pseudotyped with viral capsids from serotypes 1, 2, and 5 display differential efficiency and cell tropism after delivery to different regions of the central nervous system. Mol Ther 2004;10:302–317.PubMedGoogle Scholar
  100. 100.
    Cearley CN, Vandenberghe LH, Parente MK, et al. Expanded repertoire of AAV vector serotypes mediate unique patterns of transduction in mouse brain. Mol Ther 2008;16:1710–1718.PubMedPubMedCentralGoogle Scholar
  101. 101.
    Cearley CN, Wolfe JH. Transduction characteristics of adeno-associated virus vectors expressing cap serotypes 7, 8, 9, and Rh10 in the mouse brain. Mol Ther 2006;13:528–537.PubMedGoogle Scholar
  102. 102.
    Lawlor PA, Bland RJ, Mouravlev A, Young, During MJ. Efficient gene delivery and selective transduction of glial cells in the mammalian brain by AAV serotypes isolated from nonhuman primates. Mol Ther 2009;17:1692–1702.PubMedPubMedCentralGoogle Scholar
  103. 103.
    Yaguchi M, Ohashi Y, Tsubota T, et al. Characterization of the properties of seven promoters in the motor cortex of rats and monkeys after lentiviral vector-mediated gene transfer. Hum Gene Ther Methods 2013;24:333–344.PubMedGoogle Scholar
  104. 104.
    Miyazaki J, Takaki S, Araki K, et al. Expression vector system based on the chicken beta-actin promoter directs efficient production of interleukin-5. Gene 1989;79:269–277.PubMedGoogle Scholar
  105. 105.
    Niwa H, Yamamura K, Miyazaki J. Efficient selection for high-expression transfectants with a novel eukaryotic vector. Gene 1991;108:193–199.PubMedGoogle Scholar
  106. 106.
    Dodiya HB, Bjorklund T, Stansell J 3rd, et al. Differential transduction following basal ganglia administration of distinct pseudotyped AAV capsid serotypes in nonhuman primates. Mol Ther 2010;18:579–587.PubMedPubMedCentralGoogle Scholar
  107. 107.
    Markakis EA, Vives KP, Bober J, et al. Comparative transduction efficiency of AAV vector serotypes 1–6 in the substantia nigra and striatum of the primate brain. Mol Ther 2010;18:588–593.PubMedPubMedCentralGoogle Scholar
  108. 108.
    Passini MA, Watson DJ, Vite CH, et al. Intraventricular brain injection of adeno-associated virus type 1 (AAV1) in neonatal mice results in complementary patterns of neuronal transduction to AAV2 and total long-term correction of storage lesions in the brains of beta-glucuronidase-deficient mice. J Virol 2003;77:7034–7040.PubMedPubMedCentralGoogle Scholar
  109. 109.
    Davidson BL, Stein CS, Heth JA, et al. Recombinant adeno-associated virus type 2, 4, and 5 vectors: transduction of variant cell types and regions in the mammalian central nervous system. Proc Natl Acad Sci USA 2000;97:3428–3432.PubMedPubMedCentralGoogle Scholar
  110. 110.
    von Jonquieres G, Mersmann N, Klugmann CB, et al. Glial promoter selectivity following AAV-delivery to the immature brain. PLoS One 2013;8:e65646.Google Scholar
  111. 111.
    Dirren E, Towne CL, Setola V, et al. Intracerebroventricular injection of adeno-associated virus 6 and 9 vectors for cell type-specific transgene expression in the spinal cord. Hum Gene Ther 2014;25:109–120.PubMedGoogle Scholar
  112. 112.
    Chen H, McCarty DM, Bruce AT, Suzuki K. Oligodendrocyte-specific gene expression in mouse brain: use of a myelin-forming cell type-specific promoter in an adeno-associated virus. J Neurosci Res 1999;55:504–513.PubMedGoogle Scholar
  113. 113.
    Christine CW, Starr PA, Larson PS, et al. Safety and tolerability of putaminal AADC gene therapy for Parkinson disease. Neurology 2009;73:1662–1669.PubMedPubMedCentralGoogle Scholar
  114. 114.
    Eberling JL, Jagust WJ, Christine CW, et al. Results from a phase I safety trial of hAADC gene therapy for Parkinson disease. Neurology 2008;70:1980–1983.PubMedGoogle Scholar
  115. 115.
    Hwu WL, Muramatsu S, Tseng SH, et al. Gene therapy for aromatic l-amino acid decarboxylase deficiency. Sci Transl Med 2012;4:134ra61.PubMedGoogle Scholar
  116. 116.
    Muramatsu S, Fujimoto K, Kato S, et al. A phase I study of aromatic l-amino acid decarboxylase gene therapy for Parkinson’s disease. Mol Ther 2010;18:1731–1735.PubMedPubMedCentralGoogle Scholar
  117. 117.
    Rafii MS, Baumann TL, Bakay RA, et al. A phase1 study of stereotactic gene delivery of AAV2-NGF for Alzheimer’s disease. Alzheimers Dement, 2014 Jan 7 [Epub ahead of print].Google Scholar
  118. 118.
    Kaplitt MG, Feigin A, Tang C, et al. Safety and tolerability of gene therapy with an adeno-associated virus (AAV) borne GAD gene for Parkinson’s disease: an open label, phase I trial. Lancet 2007;369:2097–2105.PubMedGoogle Scholar
  119. 119.
    Worgall S, Sondhi D, Hackett NR, et al. Treatment of late infantile neuronal ceroid lipofuscinosis by CNS administration of a serotype 2 adeno-associated virus expressing CLN2 cDNA. Hum Gene Ther 2008;19:463–474.PubMedGoogle Scholar
  120. 120.
    Tardieu M, Zerah M, Husson B, et al. Intracerebral administration of adeno-associated viral vector serotype rh.10 carrying human SGSH and SUMF1 cDNAs in children with mucopolysaccharidosis type IIIA disease: results of a phase I/II trial. Hum Gene Ther 2014;25:506–516.PubMedGoogle Scholar
  121. 121.
    Leone P, Shera D, McPhee SE et al. Long-term follow-up after gene therapy for canavan disease. Sci Transl Med 2012;4:165ra163.PubMedPubMedCentralGoogle Scholar
  122. 122.
    Hadaczek P, Eberling JL, Pivirotto P, et al. Eight years of clinical improvement in MPTP-lesioned primates after gene therapy with AAV2-hAADC. Mol Ther 2010;18:1458–1461.PubMedPubMedCentralGoogle Scholar
  123. 123.
    Cabrera-Salazar MA, Roskelley EM, Bu J, et al. Timing of therapeutic intervention determines functional and survival outcomes in a mouse model of late infantile batten disease. Mol Ther 2007;15:1782–1788.PubMedGoogle Scholar
  124. 124.
    Ciron C, Desmaris N, Colle MA, et al. Gene therapy of the brain in the dog model of Hurler’s syndrome. Ann Neurol 2006;60:204–213.PubMedGoogle Scholar
  125. 125.
    Foust KD, Wang X, McGovern VL, et al. Rescue of the spinal muscular atrophy phenotype in a mouse model by early postnatal delivery of SMN. Nat Biotechnol 2010;28:271–274.PubMedPubMedCentralGoogle Scholar
  126. 126.
    McCurdy VJ, Johnson AK, Gray-Edwards HL, et al. Sustained normalization of neurological disease after intracranial gene therapy in a feline model. Sci Transl Med 2014;6:231ra48.PubMedGoogle Scholar
  127. 127.
    Vite CH, McGowan JC, Niogi SN, et al. Effective gene therapy for an inherited CNS disease in a large animal model. Ann Neurol 2005;57:355–364.PubMedGoogle Scholar
  128. 128.
    Fu H, Dirosario J, Killedar S, Zaraspe K, McCarty DM. Correction of neurological disease of mucopolysaccharidosis IIIB in adult mice by rAAV9 trans-blood-brain barrier gene delivery. Mol Ther 2011;19:1025–1033.PubMedPubMedCentralGoogle Scholar
  129. 129.
    Murrey DA, Naughton BJ, Duncan FJ, et al. Feasibility and safety of systemic rAAV9-hNAGLU delivery for treating mucopolysaccharidosis IIIB: toxicology, biodistribution, and immunological assessments in primates. Hum Gene Ther Clin Dev 2014;25:72–84.PubMedGoogle Scholar
  130. 130.
    Taylor RM, Wolfe JH. Decreased lysosomal storage in the adult MPS VII mouse brain in the vicinity of grafts of retroviral vector-corrected fibroblasts secreting high levels of beta-glucuronidase. Nat Med 1997;3:771–774.PubMedGoogle Scholar
  131. 131.
    Broekman ML, Tierney LA, Benn C, et al. Mechanisms of distribution of mouse beta-galactosidase in the adult GM1-gangliosidosis brain. Gene Ther 2009;16:303–308.PubMedGoogle Scholar
  132. 132.
    Passini MA, Lee EN, Heuer GG, Wolfe JH. Distribution of a lysosomal enzyme in the adult brain by axonal transport and by cells of the rostral migratory stream. J Neurosci 2002;22:6437–6446.PubMedGoogle Scholar
  133. 133.
    Cachon-Gonzalez MB, Wang SZ, McNair R, et al. Gene transfer corrects acute GM2 gangliosidosis—potential therapeutic contribution of perivascular enzyme flow. Mol Ther 2012;20:1489–1500.PubMedPubMedCentralGoogle Scholar
  134. 134.
    Vogler C, Galvin N, Levy B, et al. Transgene produces massive overexpression of human beta-glucuronidase in mice, lysosomal storage of enzyme, and strain-dependent tumors. Proc Natl Acad Sci USA 2003;100:2669–2673.PubMedPubMedCentralGoogle Scholar
  135. 135.
    Baek RC, Broekman ML, Leroy SG, et al. AAV-mediated gene delivery in adult GM1-gangliosidosis mice corrects lysosomal storage in CNS and improves survival. PLoS One 2010;5:e13468.PubMedPubMedCentralGoogle Scholar
  136. 136.
    Bradbury AM, Cochran JN, McCurdy VJ, et al. Therapeutic response in feline sandhoff disease despite immunity to intracranial gene therapy. Mol Ther 2013;21:1306–1315.PubMedPubMedCentralGoogle Scholar
  137. 137.
    Bu J, Ashe KM, Bringas J, et al. Merits of combination cortical, subcortical, and cerebellar injections for the treatment of Niemann-Pick disease type A. Mol Ther 2012;20:1893–1901.PubMedPubMedCentralGoogle Scholar
  138. 138.
    Salegio EA, Samaranch L, Jenkins RW, et al. Safety study of adeno-associated virus serotype 2-mediated human acid sphingomyelinase expression in the nonhuman primate brain. Hum Gene Ther 2012;23:891–902.PubMedPubMedCentralGoogle Scholar
  139. 139.
    Sondhi D, Johnson L, De B, et al. Long term expression and safety of administration of AAVrh.10hCLN2 to the brain of rats and non-human primates for the treatment of late infantile neuronal lipofuscinosis. Hum Gene Ther Methods 2012;23:324–335.PubMedPubMedCentralGoogle Scholar
  140. 140.
    Passini MA, Bu J, Richards AM, et al. Translational fidelity of intrathecal delivery of self-complementary AAV9-survival motor neuron 1 for spinal muscular atrophy. Hum Gene Ther 2014;25:619–630.PubMedGoogle Scholar
  141. 141.
    del Gaudio D, Fang P, Scaglia F, et al. Increased MECP2 gene copy number as the result of genomic duplication in neurodevelopmentally delayed males. Genet Med 2006;8:784–792.PubMedGoogle Scholar
  142. 142.
    Friez MJ, Jones JR, Clarkson K, et al. Recurrent infections, hypotonia, and mental retardation caused by duplication of MECP2 and adjacent region in Xq28. Pediatrics 2006;118:e1687–e1695.PubMedGoogle Scholar
  143. 143.
    Gadalla KK, Bailey ME, Spike RC, et al. Improved survival and reduced phenotypic severity following AAV9/MECP2 gene transfer to neonatal and juvenile male Mecp2 knockout mice. Mol Ther 2013;21:18–30.PubMedPubMedCentralGoogle Scholar
  144. 144.
    Garg SK, Lioy DT, Cheval H, et al. Systemic delivery of MeCP2 rescues behavioral and cellular deficits in female mouse models of Rett syndrome. J Neurosci 2013;33:13612–13620.PubMedPubMedCentralGoogle Scholar
  145. 145.
    Adachi M, Keefer EW, Jones FS. A segment of the Mecp2 promoter is sufficient to drive expression in neurons. Hum Mol Genet 2005;14:3709–3722.PubMedGoogle Scholar
  146. 146.
    McCarty DM, Monahan PE, Samulski RJ. Self-complementary recombinant adeno-associated virus (scAAV) vectors promote efficient transduction independently of DNA synthesis. Gene Ther 2001;8:1248–1254.PubMedGoogle Scholar
  147. 147.
    McCarty DM, Fu H, Monahan PE, et al. Adeno-associated virus terminal repeat (TR) mutant generates self-complementary vectors to overcome the rate-limiting step to transduction in vivo. Gene Ther 2003;10:2112–2118.PubMedGoogle Scholar
  148. 148.
    Snyder BR, Gray SJ, Quach ET, et al. Comparison of adeno-associated viral vector serotypes for spinal cord and motor neuron gene delivery. Hum Gene Ther 2011;22:1129–1135.PubMedGoogle Scholar
  149. 149.
    Gray SJ, Foti SB, Schwartz JW, et al. Optimizing promoters for recombinant adeno-associated virus-mediated gene expression in the peripheral and central nervous system using self-complementary vectors. Hum Gene Ther 2011;22:1143–1153.PubMedPubMedCentralGoogle Scholar
  150. 150.
    Brenner M, Kisseberth WC, Su Y, Besnard F, Messing A. GFAP promoter directs astrocyte-specific expression in transgenic mice. J Neurosci 1994;14:1030–1037.PubMedGoogle Scholar
  151. 151.
    Lee Y, Messing A, Su M, Brenner M. GFAP promoter elements required for region-specific and astrocyte-specific expression. Glia 2008;56:481–493.PubMedGoogle Scholar
  152. 152.
    Xu R, Janson CG, Mastakov M, et al. Quantitative comparison of expression with adeno-associated virus (AAV-2) brain-specific gene cassettes. Gene Ther 2001;8:1323–1332.PubMedGoogle Scholar
  153. 153.
    Hickman SE, Kingery ND, Ohsumi TK, et al. The microglial sensome revealed by direct RNA sequencing. Nat Neurosci 2013;16:1896–1905.PubMedGoogle Scholar
  154. 154.
    Portales-Casamar E, Swanson DJ, Liu L, et al. A regulatory toolbox of MiniPromoters to drive selective expression in the brain. Proc Natl Acad Sci USA 2010;107:16589–16594.PubMedPubMedCentralGoogle Scholar
  155. 155.
    de Leeuw CN, Dyka FM, Boye SL, et al. Targeted CNS delivery using human minipromoters and demonstrated compatibility with adeno-associated viral vectors. Mol Ther Methods Clin Dev 2014;1:5.PubMedPubMedCentralGoogle Scholar
  156. 156.
    Ferguson SM, Eskenazi D, Ishikawa M, et al. Transient neuronal inhibition reveals opposing roles of indirect and direct pathways in sensitization. Nat Neurosci 2011;14:22–24.PubMedPubMedCentralGoogle Scholar
  157. 157.
    Hikida T, Kimura K, Wada N, Funabiki K, Nakanishi S. Distinct roles of synaptic transmission in direct and indirect striatal pathways to reward and aversive behavior. Neuron 2010;66:896–907.PubMedGoogle Scholar
  158. 158.
    Flotte TR, Afione SA, Solow R, et al. Expression of the cystic fibrosis transmembrane conductance regulator from a novel adeno-associated virus promoter. J Biol Chem 1993;268:3781–3790.PubMedGoogle Scholar
  159. 159.
    Haberman RP, McCown TJ, Samulski RJ. Novel transcriptional regulatory signals in the adeno-associated virus terminal repeat A/D junction element. J Virol 2000;74:8732–8739.PubMedPubMedCentralGoogle Scholar
  160. 160.
    Hwang DY, Carlezon WA Jr, Isacson O, Kim KS. A high-efficiency synthetic promoter that drives transgene expression selectively in noradrenergic neurons. Hum Gene Ther 2001;12:1731–1740.PubMedGoogle Scholar
  161. 161.
    Bruinstroop E, Cano G, Vanderhorst VG, et al. Spinal projections of the A5, A6 (locus coeruleus), and A7 noradrenergic cell groups in rats. J Comp Neurol 2012;520:1985–2001.PubMedPubMedCentralGoogle Scholar
  162. 162.
    Persidsky, Y., S.H. Ramirez, J. Haorah, and G.D. Kanmogne, Blood-brain barrier: structural components and function under physiologic and pathologic conditions. J Neuroimmune Pharmacol 2006;1:223–236.PubMedGoogle Scholar
  163. 163.
    Abbott NJ, Ronnback L, Hansson E. Astrocyte-endothelial interactions at the blood-brain barrier. Nat Rev Neurosci 2006;7:41–53.PubMedGoogle Scholar
  164. 164.
    Miller DS. Regulation of P-glycoprotein and other ABC drug transporters at the blood-brain barrier. Trends Pharmacol Sci 2010;31:246–254.PubMedPubMedCentralGoogle Scholar
  165. 165.
    Wong HL, Chattopadhyay N, Wu XY, Bendayan R. Nanotechnology applications for improved delivery of antiretroviral drugs to the brain. Adv Drug Deliv Rev 2010;62:503–517.PubMedGoogle Scholar
  166. 166.
    Agarwal, S., P. Manchanda, M.A. Vogelbaum, J.R. Ohlfest, and W.F. Elmquist, Function of the blood-brain barrier and restriction of drug delivery to invasive glioma cells: findings in an orthotopic rat xenograft model of glioma. Drug Metab Dispos 2013;41:33–39.PubMedPubMedCentralGoogle Scholar
  167. 167.
    Lochhead JJ, Thorne RG. Intranasal delivery of biologics to the central nervous system. Adv Drug Deliv Rev 2012;64:614–628.PubMedGoogle Scholar
  168. 168.
    Sly WS, Vogler C. Brain-directed gene therapy for lysosomal storage disease: going well beyond the blood-brain barrier. Proc Natl Acad Sci USA 2002;99:5760–5762.PubMedPubMedCentralGoogle Scholar
  169. 169.
    Salvador E, Shityakov S, Forster C. Glucocorticoids and endothelial cell barrier function. Cell Tissue Res 2014;355:597–605.PubMedPubMedCentralGoogle Scholar
  170. 170.
    Schou J, Prockop LD, Dahlstrom G, Rohde C. Penetration of delta-9-tetrahydrocannabinol and 11-OH-delta-9-tetrahydrocannabinol through the blood-brain barrier. Acta Pharmacol Toxicol (Copenh) 1977;41:33–38.Google Scholar
  171. 171.
    Banks WA, Freed EO, Wolf KM, et al. Transport of human immunodeficiency virus type 1 pseudoviruses across the blood-brain barrier: role of envelope proteins and adsorptive endocytosis. J Virol 2001;75:4681–4691.PubMedPubMedCentralGoogle Scholar
  172. 172.
    Banks WA, Robinson SM, Wolf KM, Bess JW Jr, Arthur LO. Binding, internalization, and membrane incorporation of human immunodeficiency virus-1 at the blood-brain barrier is differentially regulated. Neuroscience 2004;128:143–153.PubMedGoogle Scholar
  173. 173.
    Laakkonen JP, Engler T, Romero IA, et al. Transcellular targeting of fiber- and hexon-modified adenovirus vectors across the brain microvascular endothelial cells in vitro. PLoS One 2012;7:e45977.PubMedPubMedCentralGoogle Scholar
  174. 174.
    Smith JP, Uhernik AL, Li L, Liu Z, Drewes LR. Regulation of Mct1 by cAMP-dependent internalization in rat brain endothelial cells. Brain Res 2012;1480:1–11.PubMedPubMedCentralGoogle Scholar
  175. 175.
    Boado RJ, Pardridge WM. The Trojan horse liposome technology for nonviral gene transfer across the blood-brain barrier. J Drug Deliv 2011;2011:296151.PubMedPubMedCentralGoogle Scholar
  176. 176.
    Miyake N, Miyake K, Yamamoto M, Hirai Y, Shimada T. Global gene transfer into the CNS across the BBB after neonatal systemic delivery of single-stranded AAV vectors. Brain Res 2011;1389:19–26.PubMedGoogle Scholar
  177. 177.
    Sykova E, Nicholson C. Diffusion in brain extracellular space. Physiol Rev 2008;88:1277–1340.PubMedPubMedCentralGoogle Scholar
  178. 178.
    Varadi K, Michelfelder S, Korff T, et al. Novel random peptide libraries displayed on AAV serotype 9 for selection of endothelial cell-directed gene transfer vectors. Gene Ther 2012;19:800–809.PubMedGoogle Scholar
  179. 179.
    Wang J, Faust SM, Rabinowitz JE. The next step in gene delivery: molecular engineering of adeno-associated virus serotypes. J Mol Cell Cardiol 2011;50:793–802.PubMedGoogle Scholar
  180. 180.
    Pardridge WM. Preparation of Trojan horse liposomes (THLs) for gene transfer across the blood-brain barrier. Cold Spring Harb Protoc 2010;2010:pdb prot5407.Google Scholar
  181. 181.
    Zink MC. Translational research models and novel adjunctive therapies for neuroAIDS. J Neuroimmune Pharmacol 2007;2:14–19.PubMedGoogle Scholar
  182. 182.
    Nilaver G, Muldoon LL, Kroll RA, et al. Delivery of herpesvirus and adenovirus to nude rat intracerebral tumors after osmotic blood-brain barrier disruption. Proc Natl Acad Sci USA 1995;92:9829–9833.PubMedPubMedCentralGoogle Scholar
  183. 183.
    Lacorazza HD, Flax JD, Snyder EY, Jendoubi M. Expression of human beta-hexosaminidase alpha-subunit gene (the gene defect of Tay-Sachs disease) in mouse brains upon engraftment of transduced progenitor cells. Nat Med 1996;2:424–429.PubMedGoogle Scholar
  184. 184.
    Thevenot E, Jordao JF, O’Reilly MA, et al. Targeted delivery of self-complementary adeno-associated virus serotype 9 to the brain, using magnetic resonance imaging-guided focused ultrasound. Hum Gene Ther 2012;23:1144–1155.PubMedPubMedCentralGoogle Scholar
  185. 185.
    Obermeier B, Daneman R, Ransohoff RM. Development, maintenance and disruption of the blood-brain barrier. Nat Med 2013;19:1584–1596.PubMedPubMedCentralGoogle Scholar
  186. 186.
    Sussmuth SD, Sperfeld AD, Ludolph AC, Tumani H. Hypercapnia is a possible determinant of the function of the blood-cerebrospinal fluid barrier in amyotrophic lateral sclerosis. Neurochem Res 2010;35:1071–1074.PubMedGoogle Scholar
  187. 187.
    Miyazaki K, Ohta Y, Nagai M, et al. Disruption of neurovascular unit prior to motor neuron degeneration in amyotrophic lateral sclerosis. J Neurosci Res 2011;89:718–728.PubMedGoogle Scholar
  188. 188.
    Winkler EA, Sengillo JD, Sullivan JS, et al. Blood-spinal cord barrier breakdown and pericyte reductions in amyotrophic lateral sclerosis. Acta Neuropathol 2013;125:111–120.PubMedPubMedCentralGoogle Scholar
  189. 189.
    Winkler EA, Sengillo JD, Sagare AP, et al. Blood-spinal cord barrier disruption contributes to early motor-neuron degeneration in ALS-model mice. Proc Natl Acad Sci USA 2014;111:E1035-42.PubMedPubMedCentralGoogle Scholar
  190. 190.
    Garbuzova-Davis S, Haller E, Saporta S, et al. Ultrastructure of blood-brain barrier and blood-spinal cord barrier in SOD1 mice modeling ALS. Brain Res 2007;1157:126–137.PubMedGoogle Scholar
  191. 191.
    Louboutin JP, Reyes BA, Agrawal L, et al. Blood-brain barrier abnormalities caused by exposure to HIV-1 gp120—protection by gene delivery of antioxidant enzymes. Neurobiol Dis 2010;38:313–325.PubMedGoogle Scholar
  192. 192.
    Furuno T, Landi MT, Ceroni M, et al. Expression polymorphism of the blood-brain barrier component P-glycoprotein (MDR1) in relation to Parkinson’s disease. Pharmacogenetics 2002;12:529–534.PubMedGoogle Scholar
  193. 193.
    Bartels AL, Willemsen AT, Kortekaas R, et al. Decreased blood-brain barrier P-glycoprotein function in the progression of Parkinson’s disease, PSP and MSA. J Neural Transm 2008;115:1001–1009.PubMedPubMedCentralGoogle Scholar
  194. 194.
    Schneider SW, Ludwig T, Tatenhorst L, et al. Glioblastoma cells release factors that disrupt blood-brain barrier features. Acta Neuropathol 2004;107:272–276.PubMedGoogle Scholar
  195. 195.
    Ishihara, H., H. Kubota, R.L. Lindberg, et al., Endothelial cell barrier impairment induced by glioblastomas and transforming growth factor beta2 involves matrix metalloproteinases and tight junction proteins. J Neuropathol Exp Neurol 2008;67:435–448.PubMedGoogle Scholar
  196. 196.
    Thibert KA, Raymond GV, Nascene DR, et al. Cerebrospinal fluid matrix metalloproteinases are elevated in cerebral adrenoleukodystrophy and correlate with MRI severity and neurologic dysfunction. PLoS One 2012;7:e50430.PubMedPubMedCentralGoogle Scholar
  197. 197.
    Chen YH, Chang M, Davidson BL. Molecular signatures of disease brain endothelia provide new sites for CNS-directed enzyme therapy. Nat Med 2009;15:1215–1218.PubMedPubMedCentralGoogle Scholar
  198. 198.
    Laskowitz DT, Fillit H, Yeung N, Toku K, Vitek MP. Apolipoprotein E-derived peptides reduce CNS inflammation: implications for therapy of neurological disease. Acta Neurol Scand Suppl 2006;185:15–20.PubMedGoogle Scholar
  199. 199.
    Urayama A, Grubb JH, Sly WS, Banks WA. Mannose 6-phosphate receptor-mediated transport of sulfamidase across the blood-brain barrier in the newborn mouse. Mol Ther 2008;16:1261–1266.PubMedPubMedCentralGoogle Scholar
  200. 200.
    Hsich G, Sena-Esteves M, Breakefield XO. Critical issues in gene therapy for neurologic disease. Hum Gene Ther 2002;13:579–604.PubMedGoogle Scholar
  201. 201.
    Bartus RT, Weinberg MS, Samulski RJ. Parkinson’s disease gene therapy: success by design meets failure by efficacy. Mol Ther 2014;22:487–497.PubMedPubMedCentralGoogle Scholar
  202. 202.
    Casal M, Haskins M. Large animal models and gene therapy. Eur J Hum Genet 2006;14:266–272PubMedGoogle Scholar
  203. 203.
    Manno CS, Pierce GF, Arruda VR et al. Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response. Nat Med 2006;12:342–347.PubMedGoogle Scholar
  204. 204.
    Lisowski L, Dane AP, Chu K, et al. Selection and evaluation of clinically relevant AAV variants in a xenograft liver model. Nature 2014;506:382–386.PubMedPubMedCentralGoogle Scholar
  205. 205.
    Isacson O, Breakefield XO. Benefits and risks of hosting animal cells in the human brain. Nat Med 1997;3:964–969.PubMedGoogle Scholar
  206. 206.
    Testa F, Maguire AM, Rossi S, et al. Three-year follow-up after unilateral subretinal delivery of adeno-associated virus in patients with Leber congenital Amaurosis type 2. Ophthalmology 2013;120:1283–1291.PubMedPubMedCentralGoogle Scholar
  207. 207.
    Ashtari M, Cyckowski L, Yazdi A, et al. fMRI of retina-originated phosphenes experienced by patients with leber congenital amaurosis. PLoS One 2014;9:e86068.PubMedPubMedCentralGoogle Scholar
  208. 208.
    Akil O, Seal RP, Burke K, et al. Restoration of hearing in the VGLUT3 knockout mouse using virally mediated gene therapy. Neuron 2012;75:283–293.PubMedPubMedCentralGoogle Scholar
  209. 209.
    Holt JR, Vandenberghe LH. Gene therapy for deaf mice goes viral. Mol Ther 2012;20 1836–1837.PubMedPubMedCentralGoogle Scholar
  210. 210.
    Debinski W, Tatter SB. Convection-enhanced delivery to achieve widespread distribution of viral vectors: predicting clinical implementation. Curr Opin Mol Ther 2010;12:647–653.PubMedGoogle Scholar
  211. 211.
    Wang H, Yang B, Qiu L et al. Widespread spinal cord transduction by intrathecal injection of rAAV delivers efficacious RNAi therapy for amyotrophic lateral sclerosis. Hum Mol Genet 2014;23:668–681.PubMedGoogle Scholar
  212. 212.
    Cartier N, Hacein-Bey-Abina S, Bartholomae CC, et al. Lentiviral hematopoietic cell gene therapy for X-linked adrenoleukodystrophy. Methods Enzymol 2012;507:187–198.PubMedGoogle Scholar
  213. 213.
    Ratai E, Kok T, Wiggins C, et al. Seven-Tesla proton magnetic resonance spectroscopic imaging in adult X-linked adrenoleukodystrophy. Arch Neurol 2008;65:1488–1494.PubMedPubMedCentralGoogle Scholar
  214. 214.
    Kasai K, Nakashima H, Liu F, et al. Toxicology and biodistribution studies for MGH2.1, an oncolytic virus that expresses two prodrug-activating genes, in combination with prodrugs. Mol Ther Nucleic Acids 2013;6:e113.Google Scholar
  215. 215.
    Aboody KS, Brown A, Rainov NG, et al. Neural stem cells display extensive tropism for pathology in adult brain: evidence from intracranial gliomas. Proc Natl Acad Sci USA 2000;97:12846–12851.PubMedPubMedCentralGoogle Scholar
  216. 216.
    Metz MZ, Gutova M, Lacey SF, et al. Neural stem cell-mediated delivery of irinotecan-activating carboxylesterases to glioma: implications for clinical use. Stem Cells Transl Med 2013;2:983–992.PubMedPubMedCentralGoogle Scholar
  217. 217.
    Rodríguez-Gascón A, Del Pozo-Rodríguez A, Solinís MA. Development of nucleic acid vaccines: use of self-amplifying RNA in lipid nanoparticles. Int J Nanomed 2014;9:1833–1843.Google Scholar
  218. 218.
    Mizrak A, Bolukbasi MF, Ozdener GB, et al. Genetically engineered microvesicles carrying suicide mRNA/protein inhibit schwannoma tumor growth. Mol Ther 2013;21:101–108.PubMedPubMedCentralGoogle Scholar
  219. 219.
    György B, Marcus ME, Breakefield XO, Leonard JN. Therapeutic applications of extracellular vesicles—clinical promise and open questions. Ann Rev Pharm Tox 2015:55; [Epub ahead of print].Google Scholar
  220. 220.
    Wheeler TM, Sobczak K, Lueck JD, et al. Reversal of RNA dominance by displacement of protein sequestered on triplet repeat RNA. Science 2009;325:336–339.PubMedPubMedCentralGoogle Scholar
  221. 221.
    Wheeler TM, Leger AJ, Pandey SK, et al. Targeting nuclear RNA for in vivo correction of myotonic dystrophy. Nature 2012;488:111–115.PubMedGoogle Scholar
  222. 222.
    Donnelly CJ, Zhang PW, Pham JT, et al. RNA toxicity from the ALS/FTD C9ORF72 expansion is mitigated by antisense intervention. Neuron 2013;80:415–428.PubMedPubMedCentralGoogle Scholar
  223. 223.
    Sareen D, O’Rourke JG, Meera P, et al. Targeting RNA foci in iPSC-derived motor neurons from ALS patients with a C9ORF72 repeat expansion. Sci Transl Med 2013;5:208ra149.PubMedPubMedCentralGoogle Scholar
  224. 224.
    Lagier-Tourenne C, Baughn M, Rigo F, et al. Targeted degradation of sense and antisense C9orf72 RNA foci as therapy for ALS and frontotemporal degeneration. Proc Natl Acad Sci USA 2013;110:E4530–4539.PubMedPubMedCentralGoogle Scholar
  225. 225.
    Yu D, Pendergraff H, Liu J, et al. Single-stranded RNAs use RNAi to potently and allele-selectively inhibit mutant huntingtin expression. Cell 2012;150:895–908.PubMedPubMedCentralGoogle Scholar
  226. 226.
    Kordasiewicz HB, Stanek LM, Wancewicz EV, et al. Sustained therapeutic reversal of Huntington’s disease by transient repression of huntingtin synthesis. Neuron 2012;74:1031–1044.PubMedPubMedCentralGoogle Scholar
  227. 227.
    Lieberman AP, Yu Z, Murray S, et al. Peripheral androgen receptor gene suppression rescues disease in mouse models of spinal and bulbar muscular atrophy. Cell Rep 2014;7:774–784.PubMedGoogle Scholar
  228. 228.
    Nizzardo M, Simone C, Salani S, et al. Effect of combined systemic and local morpholino treatment on the spinal muscular atrophy δ7 mouse model phenotype. Clin Ther 2014;36:340–356.PubMedGoogle Scholar
  229. 229.
    Greer KL, Lochmüller H, Flanigan K, Fletcher S, Wilton SD. Targeted exon skipping to correct exon duplications in the dystrophin gene. Mol Ther Nucleic Acids 2014;3:e155.PubMedPubMedCentralGoogle Scholar
  230. 230.
    Touznik A, Lee JJ, Yokota T. New developments in exon skipping and splice modulation therapies for neuromuscular diseases. Expert Opin Biol Ther 2014;14:809–819.PubMedGoogle Scholar
  231. 231.
    Hadinoto K, Sundaresan A, Cheow WS. Lipid-polymer hybrid nanoparticles as a new generation therapeutic delivery platform: a review. Eur J Pharm Biopharm 2013;85:427–443.PubMedGoogle Scholar
  232. 232.
    Miller TM, Pestronk A, David W, et al. An antisense oligonucleotide against SOD1 delivered intrathecally for patients with SOD1 familial amyotrophic lateral sclerosis: a phase 1, randomised, first-in-man study. Lancet Neurol 2013;12:435–442.PubMedPubMedCentralGoogle Scholar
  233. 233.
    Muntoni F, Wood MJ. Targeting RNA to treat neuromuscular disease. Nat Rev Drug Discov 2011;10:621–637.PubMedGoogle Scholar
  234. 234.
    Koo T, Wood MJ. Clinical trials using antisense oligonucleotides in duchenne muscular dystrophy. Hum Gene Ther 2013;24:479–488.PubMedGoogle Scholar
  235. 235.
    McBride JL, Pitzer MR, Boudreau RL, et al. Preclinical safety of RNAi-mediated HTT suppression in the rhesus macaque as a potential therapy for Huntington’s disease. Mol Ther 2011;19:2152–2162.PubMedPubMedCentralGoogle Scholar
  236. 236.
    Keiser MS, Boudreau RL, Davidson BL. Broad therapeutic benefit after RNAi expression vector delivery to deep cerebellar nuclei: implications for spinocerebellar ataxia type 1 therapy. Mol Ther 2014;22:588–595.PubMedGoogle Scholar
  237. 237.
    Coelho T, Adams D, Silva A, et al. Safety and efficacy of RNAi therapy for transthyretin amyloidosis. N Engl J Med 2013;369:819–829.PubMedGoogle Scholar
  238. 238.
    Cai M, Yang Y. Targeted genome editing tools for disease modeling and gene therapy. Curr Gene Ther 2014;14:2–9.PubMedGoogle Scholar
  239. 239.
    Joung JK, Sander JD TALENs: a widely applicable technology for targeted genome editing. Nat Rev Mol Cell Biol 2013;14:49–55.PubMedPubMedCentralGoogle Scholar
  240. 240.
    Ran FA, Hsu PD, Lin CY, et al. Double nicking by RNA-guided CRISPR Cas9 for enhanced genome editing specificity. Cell 2013;154:1380–1389.PubMedGoogle Scholar
  241. 241.
    Gaj T, Gersbach CA, Barbas CF. ZFN, TALEN, and CRISPR/Cas-based methods for genome engineering. Trends Biotechnol 2014;31:397–405.Google Scholar
  242. 242.
    Sanders LH, Laganière J, Cooper O, et al. LRRK2 mutations cause mitochondrial DNA damage in iPSC-derived neural cells from Parkinson’s disease patients: reversal by gene correction. Neurobiol Dis 2014;62:381–386.PubMedGoogle Scholar
  243. 243.
    Cong L, Ran FA, Cox D, et al. Multiplex genome engineering using CRISPR/Cas systems. Science 2013;339:819–823.PubMedPubMedCentralGoogle Scholar
  244. 244.
    Manjunath N, Yi G, Dang Y, Shankar P. Newer gene editing technologies toward HIV gene therapy. Viruses 2013;5:2748–2766.PubMedPubMedCentralGoogle Scholar
  245. 245.
    Yin H, Xue W, Chen S et al. Genome editing with Cas9 in adult mice corrects a disease mutation and phenotype. Nat Biotechnol 2014;32:551–553.PubMedGoogle Scholar
  246. 246.
    Maeder ML, Angstman JF, Richardson ME, et al. Targeted DNA demethylation and activation of endogenous genes using programmable TALE-TET1 fusion proteins. Nat Biotechnol 2013;31:1137–1142.PubMedGoogle Scholar
  247. 247.
    Mendenhall EM, Williamson KE, Reyon D, et al. Locus-specific editing of histone modifications at endogenous enhancers. Nat Biotechnol 2013;31:1133–1136.PubMedGoogle Scholar
  248. 248.
    Rafii MS, Baumann TL, Bakay RA, et al. A phase1 study of stereotactic gene delivery of AAV2-NGF for Alzheimer’s disease. Alzheimers Dement 2014 Jan 7 [Epub ahead of print].Google Scholar
  249. 249.
    Bartus RT, Baumann TL, Siffert J, et al. Safety/feasibility of targeting the substantia nigra with AAV2-neurturin in Parkinson patients. Neurology 2013;80:1698–1701.PubMedPubMedCentralGoogle Scholar
  250. 250.
    Bohn MC, Kozlowski DA, Connor B. Glial cell line-derived neurotrophic factor (GDNF) as a defensive molecule for neurodegenerative disease: a tribute to the studies of antonia vernadakis on neuronal-glial interactions. Int J Dev Neurosci 2000;18:679–684.PubMedGoogle Scholar
  251. 251.
    Sorenson EJ, Windbank AJ, Mandrekar JN, et al. Subcutaneous IGF-1 is not beneficial in 2-year ALS trial. Neurology 2008;71:1770–1775.PubMedPubMedCentralGoogle Scholar
  252. 252.
    Ko JH, Feigin A, Mattis PJ, et al. Network modulation following sham surgery in Parkinson’s. J Clin Invest 2014;124:3656–3666.PubMedPubMedCentralGoogle Scholar
  253. 253.
    Benraiss A, Bruel-Jungerman E, Lu G, et al. Sustained induction of neuronal addition to the adult rat neostriatum by AAV4-delivered noggin and BDNF. Gene Ther 2012;19:483–493.PubMedPubMedCentralGoogle Scholar
  254. 254.
    Hudry E, Dashkoff J, Roe AD, et al. Gene transfer of human Apoe isoforms results in differential modulation of amyloid deposition and neurotoxicity in mouse brain. Sci Transl Med 2013;5:212ra161.PubMedGoogle Scholar
  255. 255.
    Zhang W, Wang Y, Dong S, et al. Treatment of type 1 myotonic dystrophy by engineering site-specific RNA endonucleases that target (CUG)(n) repeats. Mol Ther 2014;22:312–320.PubMedGoogle Scholar
  256. 256.
    Kole R, Krainer AR, Altman S. RNA therapeutics: beyond RNA interference and antisense oligonucleotides. Nat Rev Drug Discov 2012;11:125–140.PubMedGoogle Scholar
  257. 257.
    Tang CC, Feigin A, Ma Y, et al. Metabolic network as a progression biomarker of premanifest Huntington’s disease. J Clin Invest 2013;123:4076–4088.PubMedPubMedCentralGoogle Scholar

Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc. 2014

Authors and Affiliations

  • Casey A. Maguire
    • 1
  • Servio H. Ramirez
    • 4
  • Steven F. Merkel
    • 4
  • Miguel Sena-Esteves
    • 3
  • Xandra O. Breakefield
    • 1
    • 2
  1. 1.Department of Neurology, Massachusetts General Hospital, and Neuroscience ProgramHarvard Medical SchoolCharlestownUSA
  2. 2.Department of Radiology, Massachusetts General Hospital, Neuroscience ProgramHarvard Medical SchoolBostonUSA
  3. 3.Department of NeurologyUniversity of Massachusetts Medical SchoolWorcesterUSA
  4. 4.Pathology and Laboratory MedicineTemple University School of MedicinePhiladelphiaUSA

Personalised recommendations