Gene therapy for neurological disorders: progress and prospects

  • An Erratum to this article was published on 12 September 2018

Abstract

Adeno-associated viral (AAV) vectors are a rapidly emerging gene therapy platform for the treatment of neurological diseases. In preclinical studies, transgenes encoding therapeutic proteins, microRNAs, antibodies or gene-editing machinery have been successfully delivered to the central nervous system with natural or engineered viral capsids via various routes of administration. Importantly, initial clinical studies have demonstrated encouraging safety and efficacy in diseases such as Parkinson disease and spinal muscular atrophy, as well as durability of transgene expression. Here, we discuss key considerations and challenges in the future design and development of therapeutic AAV vectors, highlighting the most promising targets and recent clinical advances.

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Figure 1: AAV engineering through high-throughput selection.
Figure 2: Recombinant AAV genome design.
Figure 3: Delivery of AAV gene therapy with intraparenchymal administration.

Change history

  • 12 September 2018

    Details related to the copyright permissions for the images shown in Figure 3 have been added to the figure legend.

References

  1. 1

    Mendell, J. R. et al. Single-dose gene-replacement therapy for spinal muscular atrophy. N. Engl. J. Med. 377, 1713–1722 (2017). This seminal clinical study demonstrates the safety and early efficacy of the first intravenously administered AAV-based therapy designed to correct the SMN deficiency in the CNS.

    CAS  Article  Google Scholar 

  2. 2

    Dominguez, E. et al. Intravenous scAAV9 delivery of a codon-optimized SMN1 sequence rescues SMA mice. Hum. Mol. Genet. 20, 681–693 (2011).

    CAS  Article  Google Scholar 

  3. 3

    Foust, K. D. et al. Rescue of the spinal muscular atrophy phenotype in a mouse model by early postnatal delivery of SMN. Nat. Biotechnol. 28, 271–274 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. 4

    Thomsen, G. M. et al. Delayed disease onset and extended survival in the SOD1G93A rat model of amyotrophic lateral sclerosis after suppression of mutant SOD1 in the motor cortex. J. Neurosci. 34, 15587–15600 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. 5

    Borel, F. et al. Therapeutic rAAVrh10 mediated SOD1 silencing in adult SOD1(G93A) mice and nonhuman primates. Hum. Gene Ther. 27, 19–31 (2016).

    CAS  Article  Google Scholar 

  6. 6

    Foust, K. D. et al. Therapeutic AAV9-mediated suppression of mutant SOD1 slows disease progression and extends survival in models of inherited ALS. Mol. Ther. 21, 2148–2159 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. 7

    McBride, J. L. et al. Artificial miRNAs mitigate shRNA-mediated toxicity in the brain: implications for the therapeutic development of RNAi. Proc. Natl Acad. Sci. USA 105, 5868–5873 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. 8

    Stanek, L. M. et al. Silencing mutant huntingtin by adeno-associated virus-mediated RNA interference ameliorates disease manifestations in the YAC128 mouse model of Huntington's disease. Hum. Gene Ther. 25, 461–474 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. 9

    Boudreau, R. L. et al. Nonallele-specific silencing of mutant and wild-type huntingtin demonstrates therapeutic efficacy in Huntington's disease mice. Mol. Ther. 17, 1053–1063 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. 10

    Hocquemiller, M., Giersch, L., Audrain, M., Parker, S. & Cartier, N. Adeno-associated virus-based gene therapy for CNS diseases. Hum. Gene Ther. 27, 478–496 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. 11

    Katz, M. L. et al. AAV gene transfer delays disease onset in a TPP1-deficient canine model of the late infantile form of Batten disease. Sci. Transl Med. 7, 313ra180 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. 12

    Rosenberg, J. B. et al. Comparative efficacy and safety of multiple routes of direct CNS administration of adeno-associated virus gene transfer vector serotype rh.10 expressing the human arylsulfatase A cDNA to nonhuman primates. Hum. Gene Ther. Clin. Dev. 25, 164–177 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. 13

    Fu, H., Dirosario, J., Killedar, S., Zaraspe, K. & McCarty, D. M. Correction of neurological disease of mucopolysaccharidosis IIIB in adult mice by rAAV9 trans-blood-brain barrier gene delivery. Mol. Ther. 19, 1025–1033 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. 14

    Weismann, C. M. et al. Systemic AAV9 gene transfer in adult GM1 gangliosidosis mice reduces lysosomal storage in CNS and extends lifespan. Hum. Mol. Genet. 24, 4353–4364 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. 15

    Bailey, R. M., Armao, D., Nagabhushan Kalburgi, S. & Gray, S. J. Development of intrathecal AAV9 gene therapy for giant axonal neuropathy. Mol. Ther. Methods Clin. Dev. 9, 160–171 (2018).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. 16

    Haurigot, V. et al. Whole body correction of mucopolysaccharidosis IIIA by intracerebrospinal fluid gene therapy. J. Clin. Invest. 123, 3254–3271 (2013).

    CAS  Article  Google Scholar 

  17. 17

    Garg, S. K. et al. Systemic delivery of MeCP2 rescues behavioral and cellular deficits in female mouse models of Rett syndrome. J. Neurosci. 33, 13612–13620 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. 18

    Gadalla, K. K. et al. Improved survival and reduced phenotypic severity following AAV9/MECP2 gene transfer to neonatal and juvenile male Mecp2 knockout mice. Mol. Ther. 21, 18–30 (2013).

    CAS  Article  Google Scholar 

  19. 19

    Gadalla, K. K. E. et al. Development of a novel AAV gene therapy cassette with improved safety features and efficacy in a mouse model of Rett syndrome. Mol. Ther. Methods Clin. Dev. 5, 180–190 (2017).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. 20

    Valori, C. F. et al. Systemic delivery of scAAV9 expressing SMN prolongs survival in a model of spinal muscular atrophy. Sci. Transl Med. 2, 35ra42 (2010).

    Article  CAS  Google Scholar 

  21. 21

    Gerard, C. et al. An AAV9 coding for frataxin clearly improved the symptoms and prolonged the life of Friedreich ataxia mouse models. Mol. Ther. Methods Clin. Dev. 1, 14044 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. 22

    Liu, W. et al. Vectored intracerebral immunization with the anti-tau monoclonal antibody PHF1 markedly reduces tau pathology in mutant tau transgenic mice. J. Neurosci. 36, 12425–12435 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. 23

    Ising, C. et al. AAV-mediated expression of anti-tau scFvs decreases tau accumulation in a mouse model of tauopathy. J. Exp. Med. 214, 1227–1238 (2017).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. 24

    Swiech, L. et al. In vivo interrogation of gene function in the mammalian brain using CRISPR-Cas9. Nat. Biotechnol. 33, 102–106 (2015).

    CAS  Article  Google Scholar 

  25. 25

    Suzuki, K. et al. In vivo genome editing via CRISPR/Cas9 mediated homology-independent targeted integration. Nature 540, 144–149 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. 26

    Davidson, B. L. 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 97, 3428–3432 (2000).

    CAS  Article  Google Scholar 

  27. 27

    Klein, R. L., Dayton, R. D., Tatom, J. B., Henderson, K. M. & Henning, P. P. AAV8, 9, Rh10, Rh43 vector gene transfer in the rat brain: effects of serotype, promoter and purification method. Mol. Ther. 16, 89–96 (2008).

    CAS  Article  Google Scholar 

  28. 28

    Hutson, T. H., Verhaagen, J., Yáñez-Muñoz, R. J. & Moon, L. D. F. Corticospinal tract transduction: a comparison of seven adeno-associated viral vector serotypes and a non-integrating lentiviral vector. Gene Ther. 19, 49–60 (2012).

    CAS  Article  Google Scholar 

  29. 29

    Bartlett, J. S., Samulski, R. J. & McCown, T. J. Selective and rapid uptake of adeno-associated virus type 2 in brain. Hum. Gene Ther. 9, 1181–1186 (1998).

    CAS  Article  Google Scholar 

  30. 30

    Burger, C. 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. 10, 302–317 (2004).

    CAS  Article  Google Scholar 

  31. 31

    Passini, M. A. Intracranial delivery of CLN2 reduces brain pathology in a mouse model of classical late infantile neuronal ceroid lipofuscinosis. J. Neurosci. 26, 1334–1342 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. 32

    Passini, M. 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 β-glucuronidase-deficient mice. J. Virol. 77, 7034 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. 33

    Federici, T. et al. Robust spinal motor neuron transduction following intrathecal delivery of AAV9 in pigs. Gene Ther. 19, 852–859 (2012).

    CAS  Article  Google Scholar 

  34. 34

    Cearley, C. N. et al. Expanded repertoire of AAV vector serotypes mediate unique patterns of transduction in mouse brain. Mol. Ther. 16, 1710–1718 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  35. 35

    Liu, G., Martins, I. H., Chiorini, J. A. & Davidson, B. L. Adeno-associated virus type 4 (AAV4) targets ependyma and astrocytes in the subventricular zone and RMS. Gene Ther. 12, 1503–1508 (2005).

    CAS  Article  Google Scholar 

  36. 36

    Taymans, J.-M. et al. Comparative analysis of adeno-associated viral vector serotypes 1, 2, 5, 7, and 8 in mouse brain. Hum. Gene Ther. 18, 195–206 (2007).

    CAS  Article  Google Scholar 

  37. 37

    Samaranch, L. et al. Strong cortical and spinal cord transduction after AAV7 and AAV9 delivery into the CSF of non-human primates. Hum. Gene Ther. 24, 526–532 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  38. 38

    Vite, C. H., Passini, M. A., Haskins, M. E. & Wolfe, J. H. Adeno-associated virus vector-mediated transduction in the cat brain. Gene Ther. 10, 1874–1881 (2003).

    CAS  Article  Google Scholar 

  39. 39

    Richardson, R. M. et al. T2 imaging in monitoring of intraparenchymal real-time convection-enhanced delivery. Neurosurgery 69, 154–163; discussion 163 (2011).

    Article  Google Scholar 

  40. 40

    Passini, M. A. et al. Translational fidelity of intrathecal delivery of self-complementary AAV9-survival motor neuron 1 for spinal muscular atrophy. Hum. Gene Ther. 25, 619–630 (2014).

    CAS  Article  Google Scholar 

  41. 41

    Miyanohara, A. et al. Potent spinal parenchymal AAV9-mediated gene delivery by subpial injection in adult rats and pigs. Mol. Ther. Methods Clin. Dev. 3, 16046 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. 42

    Gibson, L. A. et al. Adeno-associated viral gene therapy using PHP.B:NPC1 ameliorates disease phenotype in mouse model of Niemann-Pick C1 disease. Mol. Ther. 25, 1–363 (2017).

    Google Scholar 

  43. 43

    Morabito, G. et al. AAV-PHP.B-mediated global-scale expression in the mouse nervous system enables GBA1 gene therapy for wide protection from synucleinopathy. Mol. Ther. 25, 2727–2742 (2017).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  44. 44

    Balazs, A. B. et al. Antibody-based protection against HIV infection by vectored immunoprophylaxis. Nature 481, 81–84 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. 45

    Balazs, A. B., Bloom, J. D., Hong, C. M., Rao, D. S. & Baltimore, D. Broad protection against influenza infection by vectored immunoprophylaxis in mice. Nat. Biotechnol. 31, 647–652 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  46. 46

    Deverman, B. E. et al. Cre-dependent selection yields AAV variants for widespread gene transfer to the adult brain. Nat. Biotechnol. 34, 204–209 (2016). A novel, cell-type-specific, functional in vivo selection system enables the identification of several engineered AAV capsids that provide up to 40-fold greater CNS transduction than the previous standard, AAV9, after IV administration in adult mice.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  47. 47

    Ravina, B. et al. Intraputaminal AADC gene therapy for advanced Parkinson's disease: interim results of a phase 1b Trial [abstract]. Hum. Gene Ther. 28, OR12 (2017).

    Google Scholar 

  48. 48

    Hwu, W. L. et al. Gene therapy for aromatic L-amino acid decarboxylase deficiency. Sci. Transl Med. 4, 134ra61 (2012).

    Article  CAS  Google Scholar 

  49. 49

    Mittermeyer, G. et al. Long-term evaluation of a phase 1 study of AADC gene therapy for Parkinson's disease. Hum. Gene Ther. 23, 377–381 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  50. 50

    Sehara, Y. et al. Persistent expression of dopamine-synthesizing enzymes 15 years after gene transfer in a primate model of Parkinson's disease. Hum. Gene Ther. Clin. Dev. 28, 74–79 (2017).

    CAS  Article  Google Scholar 

  51. 51

    Grieger, J. C., Soltys, S. M. & Samulski, R. J. Production of recombinant adeno-associated virus vectors using suspension HEK293 cells and continuous harvest of vector from the culture media for GMP FIX and FLT1 clinical vector. Mol. Ther. 24, 287–297 (2016).

    CAS  Article  Google Scholar 

  52. 52

    Kotin, R. M. & Snyder, R. O. Manufacturing clinical grade recombinant adeno-associated virus using invertebrate cell lines. Hum. Gene Ther. 28, 350–360 (2017).

    CAS  Article  Google Scholar 

  53. 53

    Cartier, N. et al. Hematopoietic stem cell gene therapy with a lentiviral vector in X-linked adrenoleukodystrophy. Science 326, 818–823 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54

    Cartier, N. et al. Lentiviral hematopoietic cell gene therapy for X-linked adrenoleukodystrophy. Methods Enzymol. 507, 187–198 (2012).

    CAS  Article  Google Scholar 

  55. 55

    Petrs-Silva, H. et al. High-efficiency transduction of the mouse retina by tyrosine-mutant AAV serotype vectors. Mol. Ther. 17, 463–471 (2009).

    CAS  Article  Google Scholar 

  56. 56

    Lisowski, L. et al. Selection and evaluation of clinically relevant AAV variants in a xenograft liver model. Nature 506, 382–386 (2014).

    CAS  Article  Google Scholar 

  57. 57

    Atchison, R. W., Casto, B. C. & Hammon, W. M. Adenovirus-associated defective virus particles. Science 149, 754–756 (1965). The first identification of small viruses now known as AAVs as contaminants of adenovirus preparations.

    CAS  Article  Google Scholar 

  58. 58

    Hoggan, M. D., Blacklow, N. R. & Rowe, W. P. Studies of small DNA viruses found in various adenovirus preparations: physical, biological, and immunological characteristics. Proc. Natl Acad. Sci. USA 55, 1467–1474 (1966).

    CAS  Article  Google Scholar 

  59. 59

    Parks, W. P., Green, M., Pina, M. & Melnick, J. L. Physicochemical characterization of adeno-associated satellite virus type 4 and its nucleic acid. J. Virol. 1, 980–987 (1967).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60

    Chiorini, J. A., Yang, L., Liu, Y., Safer, B. & Kotin, R. M. Cloning of adeno-associated virus type 4 (AAV4) and generation of recombinant AAV4 particles. J. Virol. 71, 6823–6833 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61

    Handa, A., Muramatsu, S., Qiu, J., Mizukami, H. & Brown, K. E. Adeno-associated virus (AAV)-3-based vectors transduce haematopoietic cells not susceptible to transduction with AAV-2-based vectors. J. Gen. Virol. 81, 2077–2084 (2000).

    CAS  Article  Google Scholar 

  62. 62

    Gao, G. et al. Clades of adeno-associated viruses are widely disseminated in human tissues. J. Virol. 78, 6381–6388 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  63. 63

    Gao, G. et al. Adeno-associated viruses undergo substantial evolution in primates during natural infections. Proc. Natl Acad. Sci. USA 100, 6081–6086 (2003).

    CAS  Article  Google Scholar 

  64. 64

    Sabatino, D. E. et al. Identification of mouse AAV capsid-specific CD8+ T cell epitopes. Mol. Ther. 12, 1023–1033 (2005).

    CAS  Article  Google Scholar 

  65. 65

    Arbetman, A. E. et al. Novel caprine adeno-associated virus (AAV) capsid (AAV-Go.1) is closely related to the primate AAV-5 and has unique tropism and neutralization properties. J. Virol. 79, 15238–15245 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  66. 66

    Markakis, E. A. et al. Comparative transduction efficiency of AAV vector serotypes 1–6 in the substantia nigra and striatum of the primate brain. Mol. Ther. 18, 588–593 (2010).

    CAS  Article  Google Scholar 

  67. 67

    Bevan, A. K. et al. Systemic gene delivery in large species for targeting spinal cord, brain, and peripheral tissues for pediatric disorders. Mol. Ther. 19, 1971–1980 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  68. 68

    Gray, S. J., Nagabhushan Kalburgi, S., McCown, T. J. & Jude Samulski, R. Global CNS gene delivery and evasion of anti-AAV-neutralizing antibodies by intrathecal AAV administration in non-human primates. Gene Ther. 20, 450–459 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  69. 69

    Samaranch, L. et al. Adeno-associated virus serotype 9 transduction in the central nervous system of nonhuman primates. Hum. Gene Ther. 23, 382–389 (2012).

    CAS  Article  Google Scholar 

  70. 70

    Hinderer, C. et al. Evaluation of intrathecal routes of administration for adeno-associated viral vectors in large animals. Hum. Gene Ther. 29, 15–24 (2018).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  71. 71

    Hinderer, C. et al. Widespread gene transfer in the central nervous system of cynomolgus macaques following delivery of AAV9 into the cisterna magna. Mol. Ther. Methods Clin. Dev. 1, 14051 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. 72

    Foust, K. D. et al. Intravascular AAV9 preferentially targets neonatal neurons and adult astrocytes. Nat. Biotechnol. 27, 59–65 (2009). This report is one of two studies to first demonstrate that AAV vectors can cross the BBB and provide widespread gene expression throughout the neonatal and adult CNS; this study focuses on the mouse.

    CAS  Article  Google Scholar 

  73. 73

    Duque, S. et al. Intravenous administration of self-complementary AAV9 enables transgene delivery to adult motor neurons. Mol. Ther. 17, 1187–1196 (2009). This report is one of two studies to first demonstrate that AAV vectors can cross the BBB and provide widespread gene expression throughout the neonatal and adult CNS; this study includes the cat.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  74. 74

    Wang, D. B. et al. Expansive gene transfer in the rat CNS rapidly produces amyotrophic lateral sclerosis relevant sequelae when TDP-43 is overexpressed. Mol. Ther. 18, 2064–2074 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  75. 75

    Gray, S. J. et al. Preclinical differences of intravascular AAV9 delivery to neurons and glia: a comparative study of adult mice and nonhuman primates. Mol. Ther. 19, 1058–1069 (2011). This study highlights the species-specific tropism differences between mouse and NHPs that may complicate translational efforts of engineered AAV capsids.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  76. 76

    Samaranch, L. et al. AAV9 transduction in the central nervous system of non-human primates. Hum. Gene Ther. 23, 382–389 (2012).

    CAS  Article  Google Scholar 

  77. 77

    Huang, L. Y., Halder, S. & Agbandje-McKenna, M. Parvovirus glycan interactions. Curr. Opin. Virol. 7, 108–118 (2014).

    CAS  Article  Google Scholar 

  78. 78

    Masamizu, Y. et al. Local and retrograde gene transfer into primate neuronal pathways via adeno-associated virus serotype 8 and 9. Neuroscience 193, 249–258 (2011).

    CAS  Article  Google Scholar 

  79. 79

    Huang, L. Y. et al. Characterization of the adeno-associated virus 1 and 6 sialic acid binding site. J. Virol. 90, 5219–5230 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  80. 80

    Kern, A. et al. Identification of a heparin-binding motif on adeno-associated virus type 2 capsids. J. Virol. 77, 11072–11081 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  81. 81

    Opie, S. R. et al. Identification of amino acid residues in the capsid proteins of adeno-associated virus type 2 that contribute to heparan sulfate proteoglycan binding. J. Virol. 77, 6995–7006 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  82. 82

    Wu, Z. et al. Single amino acid changes can influence titer, heparin binding, and tissue tropism in different adeno-associated virus serotypes. J. Virol. 80, 11393–11397 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  83. 83

    Shen, S., Bryant, K. D., Brown, S. M., Randell, S. H. & Asokan, A. Terminal N-linked galactose is the primary receptor for adeno-associated virus 9. J. Biol. Chem. 286, 13532–13540 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  84. 84

    Bell, C. L., Gurda, B. L., Van Vliet, K., Agbandje-Mckenna, M. & Wilson, J. M. Identification of the galactose binding domain of the AAV9 capsid. J. Virol. 86, 7326–7333 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  85. 85

    Murlidharan, G., Corriher, T., Ghashghaei, H. T. & Asokan, A. Unique glycan signatures regulate adeno-associated virus tropism in the developing brain. J. Virol. 89, 3976–3987 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  86. 86

    Adachi, K., Enoki, T., Kawano, Y., Veraz, M. & Nakai, H. Drawing a high-resolution functional map of adeno-associated virus capsid by massively parallel sequencing. Nat. Commun. 5, 3075 (2014). In this tour de force study, the authors use alanine-scanning mutagenesis and AAV genome barcoding to map onto the linear AAV capsid sequence key functional features, including glycan binding, circulating half-life and liver and other organ transduction.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. 87

    Albright, B. H. et al. Mapping the structural determinants required for AAVrh.10 transport across the blood-brain barrier. Mol. Ther. 26, 510–523 (2018).

    CAS  Article  Google Scholar 

  88. 88

    Grimm, D. et al. In vitro and in vivo gene therapy vector evolution via multispecies interbreeding and retargeting of adeno-associated viruses. J. Virol. 82, 5887–5911 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  89. 89

    Li, W. et al. Engineering and selection of shuffled AAV genomes: a new strategy for producing targeted biological nanoparticles. Mol. Ther. 16, 1252–1260 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  90. 90

    Perabo, L. et al. Combinatorial engineering of a gene therapy vector: directed evolution of adeno-associated virus. J. Gene Med. 8, 155–162 (2006).

    CAS  Article  Google Scholar 

  91. 91

    Excoffon, K. J. D. A. et al. Directed evolution of adeno-associated virus to an infectious respiratory virus. Proc. Natl Acad. Sci. USA 106, 3865–3870 (2009).

    CAS  Article  Google Scholar 

  92. 92

    Maheshri, N., Koerber, J. T., Kaspar, B. K. & Schaffer, D. V. Directed evolution of adeno-associated virus yields enhanced gene delivery vectors. Nat. Biotechnol. 24, 198–204 (2006).

    CAS  Article  Google Scholar 

  93. 93

    Muller, O. J. et al. Random peptide libraries displayed on adeno-associated virus to select for targeted gene therapy vectors. Nat. Biotechnol. 21, 1040–1046 (2003).

    Article  CAS  Google Scholar 

  94. 94

    Tervo, D. G. et al. A designer AAV variant permits efficient retrograde access to projection neurons. Neuron 92, 372–382 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  95. 95

    Dalkara, D. et al. In vivo-directed evolution of a new adeno-associated virus for therapeutic outer retinal gene delivery from the vitreous. Sci. Transl Med. 5, 189ra76 (2013).

    Article  CAS  Google Scholar 

  96. 96

    Korbelin, J. et al. A brain microvasculature endothelial cell-specific viral vector with the potential to treat neurovascular and neurological diseases. EMBO Mol. Med. 8, 609–625 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. 97

    Koerber, J. T., Maheshri, N., Kaspar, B. K. & Schaffer, D. V. Construction of diverse adeno-associated viral libraries for directed evolution of enhanced gene delivery vehicles. Nat. Protoc. 1, 701–706 (2006).

    CAS  Article  Google Scholar 

  98. 98

    Pulicherla, N. et al. Engineering liver-detargeted AAV9 vectors for cardiac and musculoskeletal gene transfer. Mol. Ther. 19, 1070–1078 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  99. 99

    Ojala, D. S. et al. In vivo selection of a computationally designed SCHEMA AAV library yields a novel variant for infection of adult neural stem cells in the SVZ. Mol. Ther. 26, 304–319 (2018).

    CAS  Article  Google Scholar 

  100. 100

    Chan, K. Y. et al. Engineered AAVs for efficient noninvasive gene delivery to the central and peripheral nervous systems. Nat. Neurosci. 20, 1172–1179 (2017).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  101. 101

    Gao, Y., Geng, L., Chen, V. P. & Brimijoin, S. Therapeutic delivery of butyrylcholinesterase by brain-wide viral gene transfer to mice. Molecules 22, E1145 (2017).

    Article  CAS  Google Scholar 

  102. 102

    Allen, W. E. et al. Global representations of goal-directed behavior in distinct cell types of mouse neocortex. Neuron 94, 891–907.e6 (2017).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  103. 103

    Jackson, K. L., Dayton, R. D., Deverman, B. E. & Klein, R. L. Better targeting, better efficiency for wide-scale neuronal transduction with the synapsin promoter and AAV-PHP.B. Front. Mol. Neurosci. 9, 116 (2016).

    PubMed  PubMed Central  Google Scholar 

  104. 104

    Matsuzaki, Y. et al. Intravenous administration of the adeno-associated virus-PHP.B capsid fails to upregulate transduction efficiency in the marmoset brain. Neurosci. Lett. 665, 182–188 (2018).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  105. 105

    Hordeaux, J. et al. The neurotropic properties of AAV-PHP.B are limited to C57BL/6J mice. Mol. Ther. 26, 664–668 (2018).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  106. 106

    Samaranch, L. et al. AAV9-mediated expression of a non-self protein in nonhuman primate central nervous system triggers widespread neuroinflammation driven by antigen-presenting cell transduction. Mol. Ther. 22, 329–337 (2014). This study highlights the risk of expressing the GFP transgene in the CNS with inflammation and immune responses as well as ataxia after direct CNS delivery in NHPs.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  107. 107

    Sah, D. et al. Translation of intravenous delivery of AAV gene therapy for the treatment of CNS diseases [abstract]. Hum. Gene Ther. 28, P209 (2017).

    Google Scholar 

  108. 108

    Sah, D. et al. Safety and increased transduction efficiency in the adult nonhuman primate central nervous system with intravenous delivery of two novel adeno-associated virus capsids [abstract 661]. Mol. Ther. (2018).

  109. 109

    Ferrari, F. K., Samulski, T., Shenk, T. & Samulski, R. J. Second-strand synthesis is a rate-limiting step for efficient transduction by recombinant adeno-associated virus vectors. J. Virol. 70, 3227–3234 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. 110

    Chen, Y. H., Claflin, K., Geoghegan, J. C. & Davidson, B. L. Sialic acid deposition impairs the utility of AAV9, but not peptide-modified AAVs for brain gene therapy in a mouse model of lysosomal storage disease. Mol. Ther. 20, 1393–1399 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  111. 111

    Lawlor, P. A., Bland, R. J., Mouravlev, A., Young, D. & During, M. J. Efficient gene delivery and selective transduction of glial cells in the mammalian brain by AAV serotypes isolated from nonhuman primates. Mol. Ther. 17, 1692–1702 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  112. 112

    von Jonquieres, G. et al. Glial promoter selectivity following AAV-delivery to the immature brain. PLoS ONE 8, e65646 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  113. 113

    Dirren, E. 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. 25, 109–120 (2014).

    CAS  Article  Google Scholar 

  114. 114

    Zolotukhin, S. et al. Recombinant adeno-associated virus purification using novel methods improves infectious titer and yield. Gene Ther. 6, 973–985 (1999). This paper describes a simple and universally applicable purification protocol for AAV comprising an iodixanol step gradient, which has become a commonly used alternative to caesium chloride gradients.

    CAS  Article  Google Scholar 

  115. 115

    Perdomini, M. et al. Prevention and reversal of severe mitochondrial cardiomyopathy by gene therapy in a mouse model of Friedreich's ataxia. Nat. Med. 20, 542–547 (2014).

    CAS  Article  Google Scholar 

  116. 116

    Miniarikova, J. et al. Design, characterization, and lead selection of therapeutic miRNAs targeting huntingtin for development of gene therapy for Huntington's disease. Mol. Ther. Nucleic Acids 5, e297 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  117. 117

    Monteys, A. M., Ebanks, S. A., Keiser, M. S. & Davidson, B. L. CRISPR/Cas9 editing of the mutant Huntingtin allele in vitro and in vivo. Mol. Ther. 25, 12–23 (2017).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  118. 118

    McPhee, S. W. et al. Immune responses to AAV in a phase I study for Canavan disease. J. Gene Med. 8, 577–588 (2006).

    CAS  Article  Google Scholar 

  119. 119

    Leone, P. et al. Long-term follow-up after gene therapy for canavan disease. Sci. Transl Med. 4, 165ra163 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. 120

    Eberling, J. L. et al. Results from a phase I safety trial of hAADC gene therapy for Parkinson disease. Neurology 70, 1980–1983 (2008). This article presents the initial results from one of the first CNS-targeted gene therapy trials and highlights the safety of IPa AAV delivery and AADC transgene expression in patients with PD.

    CAS  Article  Google Scholar 

  121. 121

    LeWitt, P. A. et al. AAV2-GAD gene therapy for advanced Parkinson's disease: a double-blind, sham-surgery controlled, randomised trial. Lancet Neurol. 10, 309–319 (2011).

    CAS  Article  Google Scholar 

  122. 122

    Bartus, R. T. et al. Issues regarding gene therapy products for Parkinson's disease: the development of CERE-120 (AAV-NTN) as one reference point. Parkinsonism Relat. Disord. 13 (Suppl. 3), S469–S477 (2007).

    Article  Google Scholar 

  123. 123

    Limberis, M. P. et al. Intranasal antibody gene transfer in mice and ferrets elicits broad protection against pandemic influenza. Sci. Transl Med. 5, 187ra72 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. 124

    Huang, X. et al. Genome editing abrogates angiogenesis in vivo. Nat. Commun. 8, 112 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. 125

    Yu, W. et al. Nrl knockdown by AAV-delivered CRISPR/Cas9 prevents retinal degeneration in mice. Nat. Commun. 8, 14716 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  126. 126

    Laoharawee, K. et al. Dose-dependent prevention of metabolic and neurologic disease in murine MPS II by ZFN-mediated in vivo genome editing. Mol. Ther. 26, 1127–1136 (2018).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  127. 127

    Zeitler, B. J. et al. Designed zinc finger protein transcription factors for single-gene regulation throughout the central nervous system [abstract 949]. Mol. Ther. (2018).

  128. 128

    Charlesworth, C. T. et al. Identification of pre-existing adaptive immunity to Cas9 proteins in humans. Preprint at bioRxiv https://doi.org/10.1101/243345 (2018).

  129. 129

    van Dyck, C. H. Anti-amyloid-beta monoclonal antibodies for Alzheimer's disease: pitfalls and promise. Biol. Psychiatry 83, 311–319 (2018).

    CAS  Article  Google Scholar 

  130. 130

    Paul, S. M. Therapeutic antibodies for brain disorders. Sci. Transl Med. 3, 84ps20 (2011).

    Article  CAS  Google Scholar 

  131. 131

    Chavez, A. et al. Highly efficient Cas9-mediated transcriptional programming. Nat. Methods 12, 326–328 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  132. 132

    Hilton, I. B. et al. Epigenome editing by a CRISPR-Cas9-based acetyltransferase activates genes from promoters and enhancers. Nat. Biotechnol. 33, 510–517 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  133. 133

    Pawluk, A. et al. Naturally occurring off-switches for CRISPR-Cas9. Cell 167, 1829–1838.e9 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  134. 134

    Kleinstiver, B. P. et al. High-fidelity CRISPR-Cas9 nucleases with no detectable genome-wide off-target effects. Nature 529, 490–495 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  135. 135

    Zetsche, B. et al. Multiplex gene editing by CRISPR-Cpf1 using a single crRNA array. Nat. Biotechnol. 35, 31–34 (2017).

    CAS  Article  Google Scholar 

  136. 136

    Chen, J. S. et al. Enhanced proofreading governs CRISPR-Cas9 targeting accuracy. Nature 550, 407–410 (2017).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  137. 137

    Gao, L. et al. Engineered Cpf1 variants with altered PAM specificities. Nat. Biotechnol. 35, 789–792 (2017).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  138. 138

    Cox, D. B. T. et al. RNA editing with CRISPR-Cas13. Science 358, 1019–1027 (2017).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  139. 139

    Abudayyeh, O. O. et al. C2c2 is a single-component programmable RNA-guided RNA-targeting CRISPR effector. Science 353, aaf5573 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. 140

    Li, X. et al. Base editing with a Cpf1-cytidine deaminase fusion. Nat. Biotechnol. 36, 324–327 (2018).

    CAS  Article  Google Scholar 

  141. 141

    Komor, A. C., Kim, Y. B., Packer, M. S., Zuris, J. A. & Liu, D. R. Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage. Nature 533, 420–424 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  142. 142

    Gaudelli, N. M. et al. Programmable base editing of A*T to G*C in genomic DNA without DNA cleavage. Nature 551, 464–471 (2017).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  143. 143

    Harmatz, P. et al. Update on phase 1/2 clinical trials for MPS I and MPS II using ZFN-mediated in vivo genome editing. Mol. Genet. Metab. 123, S59–S60 (2018).

    Article  CAS  Google Scholar 

  144. 144

    Cullen, B. R. RNAi the natural way. Nat. Genet. 37, 1163–1165 (2005).

    CAS  Article  Google Scholar 

  145. 145

    Keiser, M. S., Geoghegan, J. C., Boudreau, R. L., Lennox, K. A. & Davidson, B. L. RNAi or overexpression: alternative therapies for spinocerebellar ataxia type 1. Neurobiol. Dis. 56, 6–13 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  146. 146

    Rodriguez-Lebron, E. et al. Silencing mutant ATXN3 expression resolves molecular phenotypes in SCA3 transgenic mice. Mol. Ther. 21, 1909–1918 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  147. 147

    Tardieu, M. 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. 25, 506–516 (2014).

    CAS  Article  Google Scholar 

  148. 148

    Lee, Y., Messing, A., Su, M. & Brenner, M. GFAP promoter elements required for region-specific and astrocyte-specific expression. Glia 56, 481–493 (2008).

    Article  Google Scholar 

  149. 149

    Dimidschstein, J. et al. A viral strategy for targeting and manipulating interneurons across vertebrate species. Nat. Neurosci. 19, 1743–1749 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  150. 150

    de Leeuw, C. N. et al. rAAV-compatible MiniPromoters for restricted expression in the brain and eye. Mol. Brain 9, 52 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. 151

    Gray, S. J. 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. 22, 1143–1153 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  152. 152

    Tornoe, J., Kusk, P., Johansen, T. E. & Jensen, P. R. Generation of a synthetic mammalian promoter library by modification of sequences spacing transcription factor binding sites. Gene 297, 21–32 (2002).

    CAS  Article  Google Scholar 

  153. 153

    Adriaansen, J. et al. Reduction of arthritis following intra-articular administration of an adeno-associated virus serotype 5 expressing a disease-inducible TNF-blocking agent. Ann. Rheum. Dis. 66, 1143–1150 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  154. 154

    Geurts, J. et al. Application of a disease-regulated promoter is a safer mode of local IL-4 gene therapy for arthritis. Gene Ther. 14, 1632–1638 (2007).

    CAS  Article  Google Scholar 

  155. 155

    Chtarto, A. et al. An adeno-associated virus-based intracellular sensor of pathological nuclear factor-kappaB activation for disease-inducible gene transfer. PLoS ONE 8, e53156 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  156. 156

    Bockstael, O. et al. Intracisternal delivery of NFkappaB-inducible scAAV2/9 reveals locoregional neuroinflammation induced by systemic kainic acid treatment. Front. Mol. Neurosci. 7, 92 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  157. 157

    Shen, F. et al. Adeno-associated viral vector-mediated hypoxia-regulated VEGF gene transfer promotes angiogenesis following focal cerebral ischemia in mice. Gene Ther. 15, 30–39 (2008).

    CAS  Article  Google Scholar 

  158. 158

    Huang, M. T. & Gorman, C. M. Intervening sequences increase efficiency of RNA 3′ processing and accumulation of cytoplasmic RNA. Nucleic Acids Res. 18, 937–947 (1990).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  159. 159

    Lacy-Hulbert, A. et al. Interruption of coding sequences by heterologous introns can enhance the functional expression of recombinant genes. Gene Ther. 8, 649–653 (2001).

    CAS  Article  Google Scholar 

  160. 160

    Choi, J. H. et al. Optimization of AAV expression cassettes to improve packaging capacity and transgene expression in neurons. Mol. Brain 7, 17 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. 161

    Xie, J. et al. MicroRNA-regulated, systemically delivered rAAV9: a step closer to CNS-restricted transgene expression. Mol. Ther. 19, 526–535 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. 162

    Majowicz, A. et al. Mir-142-3p target sequences reduce transgene-directed immunogenicity following intramuscular adeno-associated virus 1 vector-mediated gene delivery. J. Gene Med. 15, 219–232 (2013).

    CAS  Article  Google Scholar 

  163. 163

    Ferreira, J. P., Overton, K. W. & Wang, C. L. Tuning gene expression with synthetic upstream open reading frames. Proc. Natl Acad. Sci. USA 110, 11284–11289 (2013).

    CAS  Article  Google Scholar 

  164. 164

    Ward, N. J. et al. Codon optimization of human factor VIII cDNAs leads to high-level expression. Blood 117, 798–807 (2011).

    CAS  Article  Google Scholar 

  165. 165

    Radcliffe, P. A. et al. Analysis of factor VIII mediated suppression of lentiviral vector titres. Gene Ther. 15, 289–297 (2008).

    CAS  Article  Google Scholar 

  166. 166

    Weinberg, M. S., Samulski, R. J. & McCown, T. J. Adeno-associated virus (AAV) gene therapy for neurological disease. Neuropharmacology 69, 82–88 (2013).

    CAS  Article  Google Scholar 

  167. 167

    Hadaczek, P. et al. Widespread AAV1- and AAV2-mediated transgene expression in the nonhuman primate brain: implications for Huntington's disease. Mol. Ther. Methods Clin. Dev. 3, 16037 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. 168

    Kells, A. P. et al. Efficient gene therapy-based method for the delivery of therapeutics to primate cortex. Proc. Natl Acad. Sci. USA 106, 2407–2411 (2009).

    CAS  Article  Google Scholar 

  169. 169

    Cearley, C. N. & Wolfe, J. H. 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. 27, 9928–9940 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  170. 170

    Castle, M. J., Gershenson, Z. T., Giles, A. R., Holzbaur, E. L. & Wolfe, J. H. Adeno-associated virus serotypes 1, 8, and 9 share conserved mechanisms for anterograde and retrograde axonal transport. Hum. Gene Ther. 25, 705–720 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  171. 171

    Green, F. et al. Axonal transport of AAV9 in nonhuman primate brain. Gene Ther. 23, 520–526 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  172. 172

    Zerah, M. et al. Intracerebral gene therapy using AAVrh.10-hARSA recombinant vector to treat patients with early-onset forms of metachromatic leukodystrophy: preclinical feasibility and safety assessments in nonhuman primates. Hum. Gene Ther. Clin. Dev. 26, 113–124 (2015).

    CAS  Article  Google Scholar 

  173. 173

    Tardieu, M. et al. Intracerebral gene therapy in children with mucopolysaccharidosis type IIIB syndrome: an uncontrolled phase 1/2 clinical trial. Lancet Neurol. 16, 712–720 (2017).

    CAS  Article  Google Scholar 

  174. 174

    Lieberman, D. M., Laske, D. W., Morrison, P. F., Bankiewicz, K. S. & Oldfield, E. H. Convection-enhanced distribution of large molecules in gray matter during interstitial drug infusion. J. Neurosurg. 82, 1021–1029 (1995).

    CAS  Article  Google Scholar 

  175. 175

    Kanaan, N. M. et al. Rationally engineered AAV capsids improve transduction and volumetric spread in the CNS. Mol. Ther. Nucleic Acids 8, 184–197 (2017).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  176. 176

    Hinderer, C. et al. Intrathecal gene therapy corrects CNS pathology in a feline model of mucopolysaccharidosis I. Mol. Ther. 22, 2018–2027 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  177. 177

    Zhang, H. 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. 19, 1440–1448 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  178. 178

    Yang, B. et al. Global CNS transduction of adult mice by intravenously delivered rAAVrh.8 and rAAVrh.10 and nonhuman primates by rAAVrh.10. Mol. Ther. 22, 1299–1309 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  179. 179

    Varadi, K. et al. Novel random peptide libraries displayed on AAV serotype 9 for selection of endothelial cell-directed gene transfer vectors. Gene Ther. 19, 800–809 (2012).

    CAS  Article  Google Scholar 

  180. 180

    Hinderer, C. et al. Severe toxicity in nonhuman primates and piglets following high-dose intravenous administration of an adeno-associated virus vector expressing human SMN. Hum. Gene Ther. 29, 285–298 (2018).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  181. 181

    Kondratov, O. et al. Direct head-to-head evaluation of recombinant adeno-associated viral vectors manufactured in human versus insect cells. Mol. Ther. 25, 2661–2675 (2017).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  182. 182

    Adamson-Small, L. et al. A scalable method for the production of high-titer and high-quality adeno-associated type 9 vectors using the HSV platform. Mol. Ther. Methods Clin. Dev. 3, 16031 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. 183

    Conway, J. E. et al. High-titer recombinant adeno-associated virus production utilizing a recombinant herpes simplex virus type I vector expressing AAV-2 Rep and Cap. Gene Ther. 6, 986–993 (1999).

    CAS  Article  Google Scholar 

  184. 184

    Clément, N., Knop, D. R. & Byrne, B. J. Large-scale adeno-associated viral vector production using a herpesvirus-based system enables manufacturing for clinical studies. Hum. Gene Ther. 20, 796–806 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. 185

    Liu, X., Voulgaropoulou, F., Chen, R., Johnson, P. R. & Clark, K. R. Selective Rep-Cap gene amplification as a mechanism for high-titer recombinant AAV production from stable cell lines. Mol. Ther. 2, 394–403 (2000).

    CAS  Article  Google Scholar 

  186. 186

    Clark, K. R., Voulgaropoulou, F. & Johnson, P. R. A stable cell line carrying adenovirus-inducible rep and cap genes allows for infectivity titration of adeno-associated virus vectors. Gene Ther. 3, 1124–1132 (1996).

    CAS  PubMed  Google Scholar 

  187. 187

    Clark, K. R., Voulgaropoulou, F., Fraley, D. M. & Johnson, P. R. Cell lines for the production of recombinant adeno-associated virus. Hum. Gene Ther. 6, 1329–1341 (1995).

    CAS  Article  Google Scholar 

  188. 188

    Dunbar, C. E. et al. Gene therapy comes of age. Science 359, eaan4672 (2018).

    Article  CAS  Google Scholar 

  189. 189

    Zhao, L. et al. Intracerebral adeno-associated virus gene delivery of apolipoprotein E2 markedly reduces brain amyloid pathology in Alzheimer's disease mouse models. Neurobiol. Aging 44, 159–172 (2016).

    CAS  Article  Google Scholar 

  190. 190

    Bartus, R. T. & Johnson, E. M. Jr. Clinical tests of neurotrophic factors for human neurodegenerative diseases, part 1: where have we been and what have we learned? Neurobiol. Dis. 97, 156–168 (2017).

    CAS  Article  Google Scholar 

  191. 191

    Glass, J. D. et al. Transplantation of spinal cord-derived neural stem cells for ALS: analysis of phase 1 and 2 trials. Neurology 87, 392–400 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  192. 192

    Li, C. et al. Neutralizing antibodies against adeno-associated virus examined prospectively in pediatric patients with hemophilia. Gene Ther. 19, 288–294 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  193. 193

    Halbert, C. L. et al. Prevalence of neutralizing antibodies against adeno-associated virus (AAV) types 2, 5, and 6 in cystic fibrosis and normal populations: implications for gene therapy using AAV vectors. Hum. Gene Ther. 17, 440–447 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  194. 194

    Calcedo, R. et al. Adeno-associated virus antibody profiles in newborns, children, and adolescents. Clin. Vaccine Immunol. 18, 1586–1588 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  195. 195

    Lugtenberg, D. et al. Chromosomal copy number changes in patients with non-syndromic X linked mental retardation detected by array CGH. J. Med. Genet. 43, 362–370 (2006).

    CAS  Article  Google Scholar 

  196. 196

    Hanchard, N. A. et al. A partial MECP2 duplication in a mildly affected adult male: a putative role for the 3' untranslated region in the MECP2 duplication phenotype. BMC Med. Genet. 13, 71 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  197. 197

    Friez, M. J. et al. Recurrent infections, hypotonia, and mental retardation caused by duplication of MECP2 and adjacent region in Xq28. Pediatrics 118, e1687-95 (2006).

    Article  Google Scholar 

  198. 198

    Van Esch, H. et al. Duplication of the MECP2 region is a frequent cause of severe mental retardation and progressive neurological symptoms in males. Am. J. Hum. Genet. 77, 442–453 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  199. 199

    Meins, M. et al. Submicroscopic duplication in Xq28 causes increased expression of the MECP2 gene in a boy with severe mental retardation and features of Rett syndrome. J. Med. Genet. 42, e12 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  200. 200

    Ariani, F. et al. Real-time quantitative PCR as a routine method for screening large rearrangements in Rett syndrome: report of one case of MECP2 deletion and one case of MECP2 duplication. Hum. Mutat. 24, 172–177 (2004).

    CAS  Article  Google Scholar 

  201. 201

    Na, E. S. et al. A mouse model for MeCP2 duplication syndrome: MeCP2 overexpression impairs learning and memory and synaptic transmission. J. Neurosci. 32, 3109–3117 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  202. 202

    Nasir, J. et al. Targeted disruption of the Huntington's disease gene results in embryonic lethality and behavioral and morphological changes in heterozygotes. Cell 81, 811–823 (1995).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  203. 203

    White, J. K. et al. Huntingtin is required for neurogenesis and is not impaired by the Huntington's disease CAG expansion. Nat. Genet. 17, 404–410 (1997).

    CAS  Article  Google Scholar 

  204. 204

    McBride, J. L. et al. Preclinical safety of RNAi-mediated HTT suppression in the rhesus macaque as a potential therapy for Huntington's disease. Mol. Ther. 19, 2152–2162 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  205. 205

    Benatar, M. et al. Randomized, double-blind, placebo-controlled trial of arimoclomol in rapidly progressive SOD1 ALS. Neurology 90, e565–e574 (2018).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  206. 206

    Ross, C. A. et al. Huntington disease: natural history, biomarkers and prospects for therapeutics. Nat. Rev. Neurol. 10, 204–216 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  207. 207

    Bateman, R. J. et al. Clinical and biomarker changes in dominantly inherited Alzheimer's disease. N. Engl. J. Med. 367, 795–804 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  208. 208

    Kolb, S. J. et al. Natural history of infantile-onset spinal muscular atrophy. Ann. Neurol. 82, 883–891 (2017).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  209. 209

    Finkel, R. S. et al. Nusinersen versus sham control in infantile-onset spinal muscular atrophy. N. Engl. J. Med. 377, 1723–1732 (2017).

    CAS  Article  Google Scholar 

  210. 210

    Summerford, C., Bartlett, J. S. & Samulski, R. J. AlphaVbeta5 integrin: a co-receptor for adeno-associated virus type 2 infection. Nat. Med. 5, 78–82 (1999).

    CAS  Article  Google Scholar 

  211. 211

    Ling, C. et al. Human hepatocyte growth factor receptor is a cellular coreceptor for adeno-associated virus serotype 3. Hum. Gene Ther. 21, 1741–1747 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  212. 212

    Di Pasquale, G. et al. Identification of PDGFR as a receptor for AAV-5 transduction. Nat. Med. 9, 1306–1312 (2003).

    CAS  Article  Google Scholar 

  213. 213

    Akache, B. et al. The 37/67-kilodalton laminin receptor is a receptor for adeno-associated virus serotypes 8, 2, 3, and 9. J. Virol. 80, 9831–9836 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  214. 214

    Dudek, A. M. et al. An alternate route for adeno-associated virus entry independent of AAVR. J. Virol. 92, e02213-17 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  215. 215

    Pillay, S. et al. AAV serotypes have distinctive interactions with domains of the cellular receptor AAVR. J. Virol. 91, e00391-17 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  216. 216

    Bleker, S., Sonntag, F. & Kleinschmidt, J. A. Mutational analysis of narrow pores at the fivefold symmetry axes of adeno-associated virus type 2 capsids reveals a dual role in genome packaging and activation of phospholipase A2 activity. J. Virol. 79, 2528–2540 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  217. 217

    Grieger, J. C., Johnson, J. S., Gurda-Whitaker, B., Agbandje-Mckenna, M. & Samulski, R. J. Surface-exposed adeno-associated virus Vp1-NLS capsid fusion protein rescues infectivity of noninfectious wild-type Vp2/Vp3 and Vp3-only capsids but not that of fivefold pore mutant virions. J. Virol. 81, 7833–7843 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  218. 218

    Grieger, J. C., Snowdy, S. & Samulski, R. J. Separate basic region motifs within the adeno-associated virus capsid proteins are essential for infectivity and assembly. J. Virol. 80, 5199–5210 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  219. 219

    Salganik, M. et al. Adeno-associated virus capsid proteins may play a role in transcription and second-strand synthesis of recombinant genomes. J. Virol. 88, 1071–1079 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  220. 220

    Aydemir, F. et al. Mutants at the 2-fold interface of adeno-associated virus type 2 (AAV2) structural proteins suggest a role in viral transcription for AAV capsids. J. Virol. 90, 7196–7204 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  221. 221

    Rabinowitz, J. E. et al. Cross-packaging of a single adeno-associated virus (AAV) type 2 vector genome into multiple AAV serotypes enables transduction with broad specificity. J. Virol. 76, 791–801 (2002).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  222. 222

    Dong, J. Y., Fan, P. D. & Frizzell, R. A. Quantitative analysis of the packaging capacity of recombinant adeno-associated virus. Hum. Gene Ther. 7, 2101–2112 (1996).

    CAS  Article  Google Scholar 

  223. 223

    Wu, Z., Yang, H. & Colosi, P. Effect of genome size on AAV vector packaging. Mol. Ther. 18, 80–86 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  224. 224

    Miao, C. H. et al. Nonrandom transduction of recombinant adeno-associated virus vectors in mouse hepatocytes in vivo: cell cycling does not influence hepatocyte transduction. J. Virol. 74, 3793–3803 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  225. 225

    Hirata, R. K. & Russell, D. W. Design and packaging of adeno-associated virus gene targeting vectors. J. Virol. 74, 4612–4620 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  226. 226

    McCarty, D. M. 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. 10, 2112–2118 (2003). This paper presents the first study to describe the now commonly used self-complementary AAV vectors that improve the rate and efficiency of transduction by overcoming the requirement for second-strand synthesis.

    CAS  Article  Google Scholar 

  227. 227

    Nathwani, A. C. et al. Long-term safety and efficacy following systemic administration of a self-complementary AAV vector encoding human FIX pseudotyped with serotype 5 and 8 capsid proteins. Mol. Ther. 19, 876–885 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  228. 228

    Valles, F. et al. Qualitative imaging of adeno-associated virus serotype 2-human aromatic L-amino acid decarboxylase gene therapy in a phase I study for the treatment of Parkinson disease. Neurosurgery 67, 1377–1385 (2010).

    Article  Google Scholar 

  229. 229

    Bankiewicz, K. S. et al. AAV viral vector delivery to the brain by shape-conforming MR-guided infusions. J. Control. Release 240, 434–442 (2016).

    CAS  Article  Google Scholar 

  230. 230

    Shi, Y. et al. ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature 549, 523–527 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  231. 231

    Liao, F. et al. Targeting of nonlipidated, aggregated apoE with antibodies inhibits amyloid accumulation. J. Clin. Invest. 128, 2144–2155 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  232. 232

    Dodart, J.-C. et al. Gene delivery of human apolipoprotein E alters brain Abeta burden in a mouse model of Alzheimer's disease. Proc. Natl Acad. Sci. USA 102, 1211–1216 (2005).

    CAS  Article  Google Scholar 

  233. 233

    Sevigny, J. et al. The antibody aducanumab reduces Abeta plaques in Alzheimer's disease. Nature 537, 50–56 (2016).

    CAS  Article  Google Scholar 

  234. 234

    Chiang, A. C. A. et al. Combination anti-Abeta treatment maximizes cognitive recovery and rebalances mTOR signaling in APP mice. J. Exp. Med. 215, 1349–1364 (2018).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  235. 235

    Arrant, A. E., Onyilo, V. C., Unger, D. E. & Roberson, E. D. Progranulin gene therapy improves lysosomal dysfunction and microglial pathology associated with frontotemporal dementia and neuronal ceroid lipofuscinosis. J. Neurosci. 38, 2341–2358 (2018).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  236. 236

    Mis, M. S. C. et al. Development of therapeutics for C9ORF72 ALS/FTD-related disorders. Mol. Neurobiol. 54, 4466–4476 (2017).

    CAS  Article  Google Scholar 

  237. 237

    Choudhury, S. R. et al. Widespread central nervous system gene transfer and silencing after systemic delivery of novel AAV-AS vector. Mol. Ther. 24, 726–735 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  238. 238

    Muramatsu, S. et al. A phase I study of aromatic L-amino acid decarboxylase gene therapy for Parkinson's disease. Mol. Ther. 18, 1731–1735 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  239. 239

    Rocha, E. M. et al. Glucocerebrosidase gene therapy prevents alpha-synucleinopathy of midbrain dopamine neurons. Neurobiol. Dis. 82, 495–503 (2015).

    CAS  Article  Google Scholar 

  240. 240

    Bae, E. J. et al. Antibody-aided clearance of extracellular alpha-synuclein prevents cell-to-cell aggregate transmission. J. Neurosci. 32, 13454–13469 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  241. 241

    Lee, J. S. & Lee, S. J. Mechanism of anti-alpha-synuclein immunotherapy. J. Mov. Disord. 9, 14–19 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  242. 242

    Khodr, C. E. et al. An alpha-synuclein AAV gene silencing vector ameliorates a behavioral deficit in a rat model of Parkinson's disease, but displays toxicity in dopamine neurons. Brain Res. 1395, 94–107 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  243. 243

    Zharikov, A. D. et al. shRNA targeting alpha-synuclein prevents neurodegeneration in a Parkinson's disease model. J. Clin. Invest. 125, 2721–2735 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  244. 244

    Ramachandran, P. S., Boudreau, R. L., Schaefer, K. A., La Spada, A. R. & Davidson, B. L. Nonallele specific silencing of ataxin-7 improves disease phenotypes in a mouse model of SCA7. Mol. Ther. 22, 1635–1642 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  245. 245

    Biferi, M. G. et al. A new AAV10-U7-mediated gene therapy prolongs survival and restores function in an ALS mouse model. Mol. Ther. 25, 2038–2052 (2017).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  246. 246

    Towne, C., Setola, V., Schneider, B. L. & Aebischer, P. Neuroprotection by gene therapy targeting mutant SOD1 in individual pools of motor neurons does not translate into therapeutic benefit in fALS mice. Mol. Ther. 19, 274–283 (2011).

    CAS  Article  Google Scholar 

  247. 247

    Wang, H. et al. Widespread spinal cord transduction by intrathecal injection of rAAV delivers efficacious RNAi therapy for amyotrophic lateral sclerosis. Hum. Mol. Genet. 23, 668–681 (2014).

    CAS  Article  Google Scholar 

  248. 248

    Scotter, E. L., Chen, H. J. & Shaw, C. E. TDP-43 proteinopathy and ALS: insights into disease mechanisms and therapeutic targets. Neurotherapeutics 12, 352–363 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  249. 249

    Cai, W. et al. shRNA mediated knockdown of Nav1.7 in rat dorsal root ganglion attenuates pain following burn injury. BMC Anesthesiol. 16, 59 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors thank their colleagues at Voyager Therapeutics for numerous discussions on adeno-associated viral (AAV) gene therapy for central nervous system (CNS) disorders and the Parkinson disease team and P. Larson for their work on the delivery of AAV2–aromatic-L-amino-acid decarboxylase (AADC) gene therapy in patients with Parkinson disease with intraparenchymal brain administration. The authors also thank E. Smith, W. Yen and M. Lawrence for assistance with the figures, tables and text, respectively. B.E.D. was supported by the Beckman Institute for the CLARITY, Optogenetics and Vector Engineering Research Center (CLOVER) at the California Institute of Technology, the Friedreich's Ataxia Research Alliance (FARA) and FARA Australasia and the CHDI Foundation and is currently supported by the Stanley Center for Psychiatric Research at Broad Institute. K.S.B. was supported by the Michael J. Fox Foundation. B.M.R., S.M.P. and D.W.Y.S. are currently employees of Voyager Therapeutics, a CNS gene therapy company working on AAV vectors for the treatment of severe neurological diseases.

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Correspondence to Dinah W. Y. Sah.

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The authors declare competing financial interests in the form of funding from Voyager Therapeutics, employment by Voyager Therapeutics and/or personal financial interests in Voyager Therapeutics.

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Glossary

Capsid

The protein shell of the virus that protects the adeno-associated viral genome and mediates entry into and trafficking within the host cell.

Intraparenchymal

(IPa). Direct delivery of an agent into the tissue of interest.

Intrathecal

(IT). A route of access into the spinal cord cerebrospinal fluid via the space under the arachnoid membrane.

Intracerebroventricular

(ICV). A route of access into the CSF via the cerebral ventricles (typically the lateral ventricle).

Tropism

Specificity for a particular host tissue or cell type.

Serotypes

Capsid variants or groups of capsids that have distinct neutralization properties.

Intracisternal

A route of access into the CSF via the cerebellomedullary cistern.

Dependoviruses

Genus of parvoviruses that are replication-incompetent in the absence of co-infection of the host cell with a second virus such as an adenovirus or HSV.

Self-complementary AAV

An AAV genome that has been modified by elimination of the 5′ terminal resolution site and can fold into double-stranded DNA without the requirement for DNA synthesis.

Convection enhanced delivery

(CED). Infusion of adeno-associated viral vectors or other molecules into the parenchyma under positive pressure to increase the distribution volume.

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Deverman, B., Ravina, B., Bankiewicz, K. et al. Gene therapy for neurological disorders: progress and prospects. Nat Rev Drug Discov 17, 641–659 (2018). https://doi.org/10.1038/nrd.2018.110

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