Preclinical Evaluation of a Lentiviral Vector for Huntingtin Silencing

Molecular Therapy Methods and Clinical Development

Volumn 5, Issue , 2017, Pages 259-276

  Cambon, Karine ^a,b   Zimmer, Virginie ^c   Martineau, Sylvain ^a,b   Gaillard, Marie Claude ^a,b   Jarrige, Margot ^e,f   Bugi, Aurore ^f   Miniarikova, Jana ^d   Rey, Maria ^c   Hassig, Raymonde ^a,b   Dufour, Noelle ^a,b   Auregan, Gwenaelle ^a,b   Hantraye, Philippe ^a,b   Perrier, Anselme L ^e,f   Déglon, Nicole ^c  

^a Molecular Imaging Research Center   (France)

^b CNRS   (France)

^c LAUSANNE UNIVERSITY HOSPITAL   (Switzerland)

^d Department of Research & Development ^*  (Netherlands)

^e INSERM   (France)

^f I Stem   (France)

Author keywords

biosafety; gene expression; Huntington; iPSCs; off targets; RNA interference

Indexed keywords

HUNTINGTIN; LENTIVIRUS VECTOR; SHORT HAIRPIN RNA;

ARTICLE; BIOSAFETY; CORPUS STRIATUM; GENE EXPRESSION; HUMAN; HUMAN CELL; IN VITRO STUDY; IN VIVO STUDY; INDUCED PLURIPOTENT STEM CELL; NERVE CELL; PRECLINICAL STUDY; PRIORITY JOURNAL; REPORTER GENE; STEREOTAXIC SURGERY;

EID: 85020495623     PISSN: None     EISSN: 23290501     Source Type: Journal    
DOI: 10.1016/j.omtm.2017.05.001     Document Type: Article

References (121)

1. 1 Huntington, G. (1872). On chorea. The Medical and Surgical Reporter: A Weekly Journal, (Philadelphia: SW Butler) 26, 317–321.
2. 2 The Huntington's Disease Collaborative Research Group. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosome. Cell 72 (1993), 971–983.
3. 3 Godin, J.D., Colombo, K., Molina-Calavita, M., Keryer, G., Zala, D., Charrin, B.C., Dietrich, P., Volvert, M.L., Guillemot, F., Dragatsis, I., et al. Huntingtin is required for mitotic spindle orientation and mammalian neurogenesis. Neuron 67 (2010), 392–406.
4. 4 Nguyen, G.D., Gokhan, S., Molero, A.E., Mehler, M.F., Selective roles of normal and mutant huntingtin in neural induction and early neurogenesis. PLoS ONE, 8, 2013, e64368.
5. 5 Rigamonti, D., Bauer, J.H., De-Fraja, C., Conti, L., Sipione, S., Sciorati, C., Clementi, E., Hackam, A., Hayden, M.R., Li, Y., et al. Wild-type huntingtin protects from apoptosis upstream of caspase-3. J. Neurosci. 20 (2000), 3705–3713.
6. 6 Colin, E., Zala, D., Liot, G., Rangone, H., Borrell-Pagès, M., Li, X.J., Saudou, F., Humbert, S., Huntingtin phosphorylation acts as a molecular switch for anterograde/retrograde transport in neurons. EMBO J. 27 (2008), 2124–2134.
7. 7 Zala, D., Hinckelmann, M.V., Yu, H., Lyra da Cunha, M.M., Liot, G., Cordelières, F.P., Marco, S., Saudou, F., Vesicular glycolysis provides on-board energy for fast axonal transport. Cell 152 (2013), 479–491.
8. 8 Wessels, D., Lusche, D.F., Scherer, A., Kuhl, S., Myre, M.A., Soll, D.R., Huntingtin regulates Ca(2+) chemotaxis and K(+)-facilitated cAMP chemotaxis, in conjunction with the monovalent cation/H(+) exchanger Nhe1, in a model developmental system: insights into its possible role in Huntington's disease. Dev. Biol. 394 (2014), 24–38.
9. 9 Saudou, F., Humbert, S., The biology of Huntingtin. Neuron 89 (2016), 910–926.
10. 10 Hocaoglu, M.B., Gaffan, E.A., Ho, A.K., The Huntington's Disease health-related Quality of Life questionnaire (HDQoL): a disease-specific measure of health-related quality of life. Clin. Genet. 81 (2012), 117–122.
11. 11 Clay, E., De Nicola, A., Dorey, J., Squitieri, F., Aballéa, S., Martino, T., Tedroff, J., Zielonka, D., Auquier, P., Verny, C., Toumi, M., Validation of the first quality-of-life measurement for patients with Huntington's disease: the Huntington Quality of Life Instrument. Int. Clin. Psychopharmacol. 27 (2012), 208–214.
12. 12 Read, J., Jones, R., Owen, G., Leavitt, B.R., Coleman, A., Roos, R.A., Dumas, E.M., Durr, A., Justo, D., Say, M., et al., TRACK-HD investigators. Quality of life in Huntington's disease: a comparative study investigating the impact for those with pre-manifest and early manifest disease, and their partners. J. Huntingtons Dis. 2 (2013), 159–175.
13. 13 Zielonka, D., Mielcarek, M., Landwehrmeyer, G.B., Update on Huntington's disease: advances in care and emerging therapeutic options. Parkinsonism Relat. Disord. 21 (2015), 169–178.
14. 14 Harper, S.Q., Staber, P.D., He, X., Eliason, S.L., Martins, I.H., Mao, Q., Yang, L., Kotin, R.M., Paulson, H.L., Davidson, B.L., RNA interference improves motor and neuropathological abnormalities in a Huntington's disease mouse model. Proc. Natl. Acad. Sci. USA 102 (2005), 5820–5825.
15. 15 Rodriguez-Lebron, E., Denovan-Wright, E.M., Nash, K., Lewin, A.S., Mandel, R.J., Intrastriatal rAAV-mediated delivery of anti-huntingtin shRNAs induces partial reversal of disease progression in R6/1 Huntington's disease transgenic mice. Mol. Ther. 12 (2005), 618–633.
16. 16 Franich, N.R., Fitzsimons, H.L., Fong, D.M., Klugmann, M., During, M.J., Young, D., AAV vector-mediated RNAi of mutant huntingtin expression is neuroprotective in a novel genetic rat model of Huntington's disease. Mol. Ther. 16 (2008), 947–956.
17. 17 Drouet, V., Perrin, V., Hassig, R., Dufour, N., Auregan, G., Alves, S., Bonvento, G., Brouillet, E., Luthi-Carter, R., Hantraye, P., Déglon, N., Sustained effects of nonallele-specific Huntingtin silencing. Ann. Neurol. 65 (2009), 276–285.
18. 18 Nasir, J., Floresco, S.B., O'Kusky, J.R., Diewert, V.M., Richman, J.M., Zeisler, J., Borowski, A., Marth, J.D., Phillips, A.G., Hayden, M.R., Targeted disruption of the Huntington's disease gene results in embryonic lethality and behavioral and morphological changes in heterozygotes. Cell 81 (1995), 811–823.
19. 19 Duyao, M.P., Auerbach, A.B., Ryan, A., Persichetti, F., Barnes, G.T., McNeil, S.M., Ge, P., Vonsattel, J.P., Gusella, J.F., Joyner, A.L., et al. Inactivation of the mouse Huntington's disease gene homolog Hdh. Science 269 (1995), 407–410.
20. 20 Zeitlin, S., Liu, J.P., Chapman, D.L., Papaioannou, V.E., Efstratiadis, A., Increased apoptosis and early embryonic lethality in mice nullizygous for the Huntington's disease gene homologue. Nat. Genet. 11 (1995), 155–163.
21. 21 Wang, G., Liu, X., Gaertig, M.A., Li, S., Li, X.J., Ablation of huntingtin in adult neurons is nondeleterious but its depletion in young mice causes acute pancreatitis. Proc. Natl. Acad. Sci. USA 113 (2016), 3359–3364.
22. 22 DiFiglia, M., Sena-Esteves, M., Chase, K., Sapp, E., Pfister, E., Sass, M., Yoder, J., Reeves, P., Pandey, R.K., Rajeev, K.G., et al. Therapeutic silencing of mutant huntingtin with siRNA attenuates striatal and cortical neuropathology and behavioral deficits. Proc. Natl. Acad. Sci. USA 104 (2007), 17204–17209.
23. 23 Boudreau, R.L., Martins, I., Davidson, B.L., Artificial microRNAs as siRNA shuttles: improved safety as compared to shRNAs in vitro and in vivo. Mol. Ther. 17 (2009), 169–175.
24. 24 Godinho, B.M., Malhotra, M., O'Driscoll, C.M., Cryan, J.F., Delivering a disease-modifying treatment for Huntington's disease. Drug Discov. Today 20 (2015), 50–64.
25. 25 Whitehead, K.A., Langer, R., Anderson, D.G., Knocking down barriers: advances in siRNA delivery. Nat. Rev. Drug Discov. 8 (2009), 129–138.
26. 26 Brummelkamp, T.R., Bernards, R., Agami, R., A system for stable expression of short interfering RNAs in mammalian cells. Science 296 (2002), 550–553.
27. 27 Hu, X., Hipolito, S., Lynn, R., Abraham, V., Ramos, S., Wong-Staal, F., Relative gene-silencing efficiencies of small interfering RNAs targeting sense and antisense transcripts from the same genetic locus. Nucleic Acids Res. 32 (2004), 4609–4617.
28. 28 Li, L., Lin, X., Khvorova, A., Fesik, S.W., Shen, Y., Defining the optimal parameters for hairpin-based knockdown constructs. RNA 13 (2007), 1765–1774.
29. 29 Vlassov, A.V., Korba, B., Farrar, K., Mukerjee, S., Seyhan, A.A., Ilves, H., Kaspar, R.L., Leake, D., Kazakov, S.A., Johnston, B.H., shRNAs targeting hepatitis C: effects of sequence and structural features, and comparision with siRNA. Oligonucleotides 17 (2007), 223–236.
30. 30 Arvey, A., Larsson, E., Sander, C., Leslie, C.S., Marks, D.S., Target mRNA abundance dilutes microRNA and siRNA activity. Mol. Syst. Biol., 6, 2010, 363.
31. 31 Larsson, C., Grundberg, I., Söderberg, O., Nilsson, M., In situ detection and genotyping of individual mRNA molecules. Nat. Methods 7 (2010), 395–397.
32. 32 Hong, S.W., Jiang, Y., Kim, S., Li, C.J., Lee, D.K., Target gene abundance contributes to the efficiency of siRNA-mediated gene silencing. Nucleic Acid Ther. 24 (2014), 192–198.
33. 33 Larsson, E., Sander, C., Marks, D., mRNA turnover rate limits siRNA and microRNA efficacy. Mol. Syst. Biol., 6, 2010, 433.
34. 34 Holen, T., Amarzguioui, M., Wiiger, M.T., Babaie, E., Prydz, H., Positional effects of short interfering RNAs targeting the human coagulation trigger Tissue Factor. Nucleic Acids Res. 30 (2002), 1757–1766.
35. 35 Bohula, E.A., Salisbury, A.J., Sohail, M., Playford, M.P., Riedemann, J., Southern, E.M., Macaulay, V.M., The efficacy of small interfering RNAs targeted to the type 1 insulin-like growth factor receptor (IGF1R) is influenced by secondary structure in the IGF1R transcript. J. Biol. Chem. 278 (2003), 15991–15997.
36. 36 Khvorova, A., Reynolds, A., Jayasena, S.D., Functional siRNAs and miRNAs exhibit strand bias. Cell 115 (2003), 209–216.
37. 37 Kretschmer-Kazemi Far, R., Sczakiel, G., The activity of siRNA in mammalian cells is related to structural target accessibility: a comparison with antisense oligonucleotides. Nucleic Acids Res. 31 (2003), 4417–4424.
38. 38 Overhoff, M., Alken, M., Far, R.K., Lemaitre, M., Lebleu, B., Sczakiel, G., Robbins, I., Local RNA target structure influences siRNA efficacy: a systematic global analysis. J. Mol. Biol. 348 (2005), 871–881.
39. 39 McIntyre, G.J., Yu, Y.H., Lomas, M., Fanning, G.C., The effects of stem length and core placement on shRNA activity. BMC Mol. Biol., 12, 2011, 34.
40. 40 Xia, H., Mao, Q., Eliason, S.L., Harper, S.Q., Martins, I.H., Orr, H.T., Paulson, H.L., Yang, L., Kotin, R.M., Davidson, B.L., RNAi suppresses polyglutamine-induced neurodegeneration in a model of spinocerebellar ataxia. Nat. Med. 10 (2004), 816–820.
41. 41 Chen, Z.J., Kren, B.T., Wong, P.Y., Low, W.C., Steer, C.J., Sleeping Beauty-mediated down-regulation of huntingtin expression by RNA interference. Biochem. Biophys. Res. Commun. 329 (2005), 646–652.
42. 42 Huang, B., Kochanek, S., Adenovirus-mediated silencing of huntingtin expression by shRNA. Hum. Gene Ther. 16 (2005), 618–626.
43. 43 Wang, Y.L., Liu, W., Wada, E., Murata, M., Wada, K., Kanazawa, I., Clinico-pathological rescue of a model mouse of Huntington's disease by siRNA. Neurosci. Res. 53 (2005), 241–249.
44. 44 Machida, Y., Okada, T., Kurosawa, M., Oyama, F., Ozawa, K., Nukina, N., rAAV-mediated shRNA ameliorated neuropathology in Huntington disease model mouse. Biochem. Biophys. Res. Commun. 343 (2006), 190–197.
45. 45 Gary, D.S., Davidson, A., Milhavet, O., Slunt, H., Borchelt, D.R., Investigation of RNA interference to suppress expression of full-length and fragment human huntingtin. Neuromolecular Med. 9 (2007), 145–155.
46. 46 Huang, B., Schiefer, J., Sass, C., Landwehrmeyer, G.B., Kosinski, C.M., Kochanek, S., High-capacity adenoviral vector-mediated reduction of huntingtin aggregate load in vitro and in vivo. Hum. Gene Ther. 18 (2007), 303–311.
47. 47 McBride, J.L., Boudreau, R.L., Harper, S.Q., Staber, P.D., Monteys, A.M., Martins, I., Gilmore, B.L., Burstein, H., Peluso, R.W., Polisky, B., et al. Artificial miRNAs mitigate shRNA-mediated toxicity in the brain: implications for the therapeutic development of RNAi. Proc. Natl. Acad. Sci. USA 105 (2008), 5868–5873.
48. 48 Boudreau, R.L., McBride, J.L., Martins, I., Shen, S., Xing, Y., Carter, B.J., Davidson, B.L., Nonallele-specific silencing of mutant and wild-type huntingtin demonstrates therapeutic efficacy in Huntington's disease mice. Mol. Ther. 17 (2009), 1053–1063.
49. 49 Drouet, V., Ruiz, M., Zala, D., Feyeux, M., Auregan, G., Cambon, K., Troquier, L., Carpentier, J., Aubert, S., Merienne, N., et al. Allele-specific silencing of mutant huntingtin in rodent brain and human stem cells. PLoS ONE, 9, 2014, e99341.
50. 50 Grimm, D., The dose can make the poison: lessons learned from adverse in vivo toxicities caused by RNAi overexpression. Silence, 2, 2011, 8.
51. 51 Marques, J.T., Devosse, T., Wang, D., Zamanian-Daryoush, M., Serbinowski, P., Hartmann, R., Fujita, T., Behlke, M.A., Williams, B.R., A structural basis for discriminating between self and nonself double-stranded RNAs in mammalian cells. Nat. Biotechnol. 24 (2006), 559–565.
52. 52 Judge, A., MacLachlan, I., Overcoming the innate immune response to small interfering RNA. Hum. Gene Ther. 19 (2008), 111–124.
53. 53 Bennasser, Y., Chable-Bessia, C., Triboulet, R., Gibbings, D., Gwizdek, C., Dargemont, C., Kremer, E.J., Voinnet, O., Benkirane, M., Competition for XPO5 binding between Dicer mRNA, pre-miRNA and viral RNA regulates human Dicer levels. Nat. Struct. Mol. Biol. 18 (2011), 323–327.
54. 54 Grimm, D., Wang, L., Lee, J.S., Schürmann, N., Gu, S., Börner, K., Storm, T.A., Kay, M.A., Argonaute proteins are key determinants of RNAi efficacy, toxicity, and persistence in the adult mouse liver. J. Clin. Invest. 120 (2010), 3106–3119.
55. 55 McManus, M.T., Petersen, C.P., Haines, B.B., Chen, J., Sharp, P.A., Gene silencing using micro-RNA designed hairpins. RNA 8 (2002), 842–850.
56. 56 Harborth, J., Elbashir, S.M., Vandenburgh, K., Manninga, H., Scaringe, S.A., Weber, K., Tuschl, T., Sequence, chemical, and structural variation of small interfering RNAs and short hairpin RNAs and the effect on mammalian gene silencing. Antisense Nucleic Acid Drug Dev. 13 (2003), 83–105.
57. 57 Dull, T., Zufferey, R., Kelly, M., Mandel, R.J., Nguyen, M., Trono, D., Naldini, L., A third-generation lentivirus vector with a conditional packaging system. J. Virol. 72 (1998), 8463–8471.
58. 58 Christodoulou, I., Patsali, P., Stephanou, C., Antoniou, M., Kleanthous, M., Lederer, C.W., Measurement of lentiviral vector titre and copy number by cross-species duplex quantitative PCR. Gene Ther. 23 (2016), 113–118.
59. 59 Perrier, A., Peschanski, M., How can human pluripotent stem cells help decipher and cure Huntington's disease?. Cell Stem Cell 11 (2012), 153–161.
60. 60 Nicoleau, C., Varela, C., Bonnefond, C., Maury, Y., Bugi, A., Aubry, L., Viegas, P., Bourgois-Rocha, F., Peschanski, M., Perrier, A.L., Embryonic stem cells neural differentiation qualifies the role of Wnt/β-Catenin signals in human telencephalic specification and regionalization. Stem Cells 31 (2013), 1763–1774.
61. 61 Arber, C., Precious, S.V., Cambray, S., Risner-Janiczek, J.R., Kelly, C., Noakes, Z., Fjodorova, M., Heuer, A., Ungless, M.A., Rodríguez, T.A., et al. Activin A directs striatal projection neuron differentiation of human pluripotent stem cells. Development 142 (2015), 1375–1386.
62. 62 Arlotta, P., Molyneaux, B.J., Jabaudon, D., Yoshida, Y., Macklis, J.D., Ctip2 controls the differentiation of medium spiny neurons and the establishment of the cellular architecture of the striatum. J. Neurosci. 28 (2008), 622–632.
63. 63 Sussel, L., Marin, O., Kimura, S., Rubenstein, J.L., Loss of Nkx2.1 homeobox gene function results in a ventral to dorsal molecular respecification within the basal telencephalon: evidence for a transformation of the pallidum into the striatum. Development 126 (1999), 3359–3370.
64. 64 Du, T., Xu, Q., Ocbina, P.J., Anderson, S.A., NKX2.1 specifies cortical interneuron fate by activating Lhx6. Development 135 (2008), 1559–1567.
65. 65 Hevner, R.F., Shi, L., Justice, N., Hsueh, Y., Sheng, M., Smiga, S., Bulfone, A., Goffinet, A.M., Campagnoni, A.T., Rubenstein, J.L., Tbr1 regulates differentiation of the preplate and layer 6. Neuron 29 (2001), 353–366.
66. 66 Leone, D.P., Srinivasan, K., Chen, B., Alcamo, E., McConnell, S.K., The determination of projection neuron identity in the developing cerebral cortex. Curr. Opin. Neurobiol. 18 (2008), 28–35.
67. 67 Bedogni, F., Hodge, R.D., Elsen, G.E., Nelson, B.R., Daza, R.A., Beyer, R.P., Bammler, T.K., Rubenstein, J.L., Hevner, R.F., Tbr1 regulates regional and laminar identity of postmitotic neurons in developing neocortex. Proc. Natl. Acad. Sci. USA 107 (2010), 13129–13134.
68. 68 McKenna, W.L., Betancourt, J., Larkin, K.A., Abrams, B., Guo, C., Rubenstein, J.L., Chen, B., Tbr1 and Fezf2 regulate alternate corticofugal neuronal identities during neocortical development. J. Neurosci. 31 (2011), 549–564.
69. 69 Han, W., Kwan, K.Y., Shim, S., Lam, M.M., Shin, Y., Xu, X., Zhu, Y., Li, M., Sestan, N., TBR1 directly represses Fezf2 to control the laminar origin and development of the corticospinal tract. Proc. Natl. Acad. Sci. USA 108 (2011), 3041–3046.
70. 70 Ferland, R.J., Cherry, T.J., Preware, P.O., Morrisey, E.E., Walsh, C.A., Characterization of Foxp2 and Foxp1 mRNA and protein in the developing and mature brain. J. Comp. Neurol. 460 (2003), 266–279.
71. 71 Tamura, S., Morikawa, Y., Iwanishi, H., Hisaoka, T., Senba, E., Foxp1 gene expression in projection neurons of the mouse striatum. Neuroscience 124 (2004), 261–267.
72. 72 Ouimet, C.C., Langley-Gullion, K.C., Greengard, P., Quantitative immunocytochemistry of DARPP-32-expressing neurons in the rat caudatoputamen. Brain Res. 808 (1998), 8–12.
73. 73 Lopes, C., Aubert, S., Bourgois-Rocha, F., Barnat, M., Rego, A.C., Déglon, N., Perrier, A.L., Humbert, S., Dominant-negative effects of adult-onset Huntingtin mutations alter the division of human embryonic stem cells-derived neural cells. PLoS ONE, 11, 2016, e0148680.
74. 74 Kay, C., Collins, J.A., Skotte, N.H., Southwell, A.L., Warby, S.C., Caron, N.S., Doty, C.N., Nguyen, B., Griguoli, A., Ross, C.J., et al. Huntingtin haplotypes provide prioritized target panels for allele-specific silencing in Huntington disease patients of European ancestry. Mol. Ther. 23 (2015), 1759–1771.
75. 75 Rose, S.D., Kim, D.H., Amarzguioui, M., Heidel, J.D., Collingwood, M.A., Davis, M.E., Rossi, J.J., Behlke, M.A., Functional polarity is introduced by Dicer processing of short substrate RNAs. Nucleic Acids Res. 33 (2005), 4140–4156.
76. 76 Zhou, J., Song, M.S., Jacobi, A.M., Behlke, M.A., Wu, X., Rossi, J.J., Deep sequencing analyses of DsiRNAs reveal the influence of 3′ terminal overhangs on Dicing polarity, strand selectivity, and RNA editing of siRNAs. Mol. Ther. Nucleic Acids, 1, 2012, e17.
77. 77 Dallas, A., Ilves, H., Ge, Q., Kumar, P., Shorenstein, J., Kazakov, S.A., Cuellar, T.L., McManus, M.T., Behlke, M.A., Johnston, B.H., Right- and left-loop short shRNAs have distinct and unusual mechanisms of gene silencing. Nucleic Acids Res. 40 (2012), 9255–9271.
78. 78 Amarzguioui, M., Prydz, H., An algorithm for selection of functional siRNA sequences. Biochem. Biophys. Res. Commun. 316 (2004), 1050–1058.
79. 79 Naito, Y., Yamada, T., Ui-Tei, K., Morishita, S., Saigo, K., siDirect: highly effective, target-specific siRNA design software for mammalian RNA interference. Nucleic Acids Res. 32 (2004), W124–W129.
80. 80 Reynolds, A., Leake, D., Boese, Q., Scaringe, S., Marshall, W.S., Khvorova, A., Rational siRNA design for RNA interference. Nat. Biotechnol. 22 (2004), 326–330.
81. 81 Naito, Y., Yoshimura, J., Morishita, S., Ui-Tei, K., siDirect 2.0: updated software for designing functional siRNA with reduced seed-dependent off-target effect. BMC Bioinformatics, 10, 2009, 392.
82. 82 Boudreau, R.L., Spengler, R.M., Hylock, R.H., Kusenda, B.J., Davis, H.A., Eichmann, D.A., Davidson, B.L., siSPOTR: a tool for designing highly specific and potent siRNAs for human and mouse. Nucleic Acids Res., 41, 2013, e9.
83. 83 Grimm, D., Streetz, K.L., Jopling, C.L., Storm, T.A., Pandey, K., Davis, C.R., Marion, P., Salazar, F., Kay, M.A., Fatality in mice due to oversaturation of cellular microRNA/short hairpin RNA pathways. Nature 441 (2006), 537–541.
84. 84 An, D.S., Qin, F.X., Auyeung, V.C., Mao, S.H., Kung, S.K., Baltimore, D., Chen, I.S., Optimization and functional effects of stable short hairpin RNA expression in primary human lymphocytes via lentiviral vectors. Mol. Ther. 14 (2006), 494–504.
85. 85 Bauer, M., Kinkl, N., Meixner, A., Kremmer, E., Riemenschneider, M., Förstl, H., Gasser, T., Ueffing, M., Prevention of interferon-stimulated gene expression using microRNA-designed hairpins. Gene Ther. 16 (2009), 142–147.
86. 86 Hutson, T.H., Foster, E., Dawes, J.M., Hindges, R., Yáñez-Muñoz, R.J., Moon, L.D., Lentiviral vectors encoding short hairpin RNAs efficiently transduce and knockdown LINGO-1 but induce an interferon response and cytotoxicity in central nervous system neurones. J. Gene Med. 14 (2012), 299–315.
87. 87 Hutson, T.H., Foster, E., Moon, L.D., Yáñez-Muñoz, R.J., Lentiviral vector-mediated RNA silencing in the central nervous system. Hum. Gene Ther. Methods 25 (2014), 14–32.
88. 88 Lafon, M., Megret, F., Lafage, M., Prehaud, C., The innate immune facet of brain: human neurons express TLR-3 and sense viral dsRNA. J. Mol. Neurosci. 29 (2006), 185–194.
89. 89 Bridge, A.J., Pebernard, S., Ducraux, A., Nicoulaz, A.L., Iggo, R., Induction of an interferon response by RNAi vectors in mammalian cells. Nat. Genet. 34 (2003), 263–264.
90. 90 Ge, Q., Ilves, H., Dallas, A., Kumar, P., Shorenstein, J., Kazakov, S.A., Johnston, B.H., Minimal-length short hairpin RNAs: the relationship of structure and RNAi activity. RNA 16 (2010), 106–117.
91. 91 Cifuentes, D., Xue, H., Taylor, D.W., Patnode, H., Mishima, Y., Cheloufi, S., Ma, E., Mane, S., Hannon, G.J., Lawson, N.D., et al. A novel miRNA processing pathway independent of Dicer requires Argonaute2 catalytic activity. Science 328 (2010), 1694–1698.
92. 92 Cheloufi, S., Dos Santos, C.O., Chong, M.M., Hannon, G.J., A dicer-independent miRNA biogenesis pathway that requires Ago catalysis. Nature 465 (2010), 584–589.
93. 93 Yang, J.S., Maurin, T., Lai, E.C., Functional parameters of Dicer-independent microRNA biogenesis. RNA 18 (2012), 945–957.
94. 94 Yang, J.S., Maurin, T., Robine, N., Rasmussen, K.D., Jeffrey, K.L., Chandwani, R., Papapetrou, E.P., Sadelain, M., O'Carroll, D., Lai, E.C., Conserved vertebrate mir-451 provides a platform for Dicer-independent, Ago2-mediated microRNA biogenesis. Proc. Natl. Acad. Sci. USA 107 (2010), 15163–15168.
95. 95 Ma, H., Zhang, J., Wu, H., Designing Ago2-specific siRNA/shRNA to avoid competition with endogenous miRNAs. Mol. Ther. Nucleic Acids, 3, 2014, e176.
96. 96 Liu, Y.P., Schopman, N.C., Berkhout, B., Dicer-independent processing of short hairpin RNAs. Nucleic Acids Res. 41 (2013), 3723–3733.
97. 97 Martin, J.N., Wolken, N., Brown, T., Dauer, W.T., Ehrlich, M.E., Gonzalez-Alegre, P., Lethal toxicity caused by expression of shRNA in the mouse striatum: implications for therapeutic design. Gene Ther. 18 (2011), 666–673.
98. 98 Ehlert, E.M., Eggers, R., Niclou, S.P., Verhaagen, J., Cellular toxicity following application of adeno-associated viral vector-mediated RNA interference in the nervous system. BMC Neurosci., 11, 2010, 20.
99. 99 Cuccato, G., Polynikis, A., Siciliano, V., Graziano, M., di Bernardo, M., di Bernardo, D., Modeling RNA interference in mammalian cells. BMC Syst. Biol., 5, 2011, 19.
100. 100 Kalathur, R.K., Hernández-Prieto, M.A., Futschik, M.E., Huntington's disease and its therapeutic target genes: a global functional profile based on the HD Research Crossroads database. BMC Neurol., 12, 2012, 47.
101. 101 Valenza, M., Rigamonti, D., Goffredo, D., Zuccato, C., Fenu, S., Jamot, L., Strand, A., Tarditi, A., Woodman, B., Racchi, M., et al. Dysfunction of the cholesterol biosynthetic pathway in Huntington's disease. J. Neurosci. 25 (2005), 9932–9939.
102. 102 Li, P., Nie, Y., Yu, J., An effective method to identify shared pathways and common factors among neurodegenerative diseases. PLoS ONE, 10, 2015, e0143045.
103. 103 Elias, S., McGuire, J.R., Yu, H., Humbert, S., Huntingtin is required for epithelial polarity through RAB11A-mediated apical trafficking of PAR3-aPKC. PLoS Biol., 13, 2015, e1002142.
104. 104 Olejniczak, M., Urbanek, M.O., Jaworska, E., Witucki, L., Szczesniak, M.W., Makalowska, I., Krzyzosiak, W.J., Sequence-non-specific effects generated by various types of RNA interference triggers. Biochim. Biophys. Acta 1859 (2016), 306–314.
105. 105 Pebernard, S., Iggo, R.D., Determinants of interferon-stimulated gene induction by RNAi vectors. Differentiation 72 (2004), 103–111.
106. 106 McBride, J.L., Pitzer, M.R., Boudreau, R.L., Dufour, B., Hobbs, T., Ojeda, S.R., Davidson, B.L., Preclinical safety of RNAi-mediated HTT suppression in the rhesus macaque as a potential therapy for Huntington's disease. Mol. Ther. 19 (2011), 2152–2162.
107. 107 Grondin, R., Kaytor, M.D., Ai, Y., Nelson, P.T., Thakker, D.R., Heisel, J., Weatherspoon, M.R., Blum, J.L., Burright, E.N., Zhang, Z., Kaemmerer, W.F., Six-month partial suppression of Huntingtin is well tolerated in the adult rhesus striatum. Brain 135 (2012), 1197–1209.
108. 108 Lombardi, M.S., Jaspers, L., Spronkmans, C., Gellera, C., Taroni, F., Di Maria, E., Donato, S.D., Kaemmerer, W.F., A majority of Huntington's disease patients may be treatable by individualized allele-specific RNA interference. Exp. Neurol. 217 (2009), 312–319.
109. 109 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 (2017), 12–23.
110. 110 Shin, J.W., Kim, K.H., Chao, M.J., Atwal, R.S., Gillis, T., MacDonald, M.E., Gusella, J.F., Lee, J.M., Permanent inactivation of Huntington's disease mutation by personalized allele-specific CRISPR/Cas9. Hum. Mol. Genet. 25 (2016), 4566–4576.
111. 111 Chung, D.W., Rudnicki, D.D., Yu, L., Margolis, R.L., A natural antisense transcript at the Huntington's disease repeat locus regulates HTT expression. Hum. Mol. Genet. 20 (2011), 3467–3477.
112. 112 Palfi, S., Brouillet, E., Jarraya, B., Bloch, J., Jan, C., Shin, M., Condé, F., Li, X.J., Aebischer, P., Hantraye, P., Déglon, N., Expression of mutated huntingtin fragment in the putamen is sufficient to produce abnormal movement in non-human primates. Mol. Ther. 15 (2007), 1444–1451.
113. 113 Hirano, M., Kato, S., Kobayashi, K., Okada, T., Yaginuma, H., Kobayashi, K., Highly efficient retrograde gene transfer into motor neurons by a lentiviral vector pseudotyped with fusion glycoprotein. PLoS ONE, 8, 2013, e75896.
114. 114 Bankiewicz, K.S., Sudhakar, V., Samaranch, L., San Sebastian, W., Bringas, J., Forsayeth, J., AAV viral vector delivery to the brain by shape-conforming MR-guided infusions. J. Control. Release 240 (2016), 434–442.
115. 115 Hintiryan, H., Foster, N.N., Bowman, I., Bay, M., Song, M.Y., Gou, L., Yamashita, S., Bienkowski, M.S., Zingg, B., Zhu, M., et al. The mouse cortico-striatal projectome. Nat. Neurosci. 19 (2016), 1100–1114.
116. 116 Follenzi, A., Ailles, L.E., Bakovic, S., Geuna, M., Naldini, L., Gene transfer by lentiviral vectors is limited by nuclear translocation and rescued by HIV-1 pol sequences. Nat. Genet. 25 (2000), 217–222.
117. 117 Déglon, N., Tseng, J.L., Bensadoun, J.C., Zurn, A.D., Arsenijevic, Y., Pereira de Almeida, L., Zufferey, R., Trono, D., Aebischer, P., Self-inactivating lentiviral vectors with enhanced transgene expression as potential gene transfer system in Parkinson's disease. Hum. Gene Ther. 11 (2000), 179–190.
118. 118 de Almeida, L.P., Ross, C.A., Zala, D., Aebischer, P., Déglon, N., Lentiviral-mediated delivery of mutant huntingtin in the striatum of rats induces a selective neuropathology modulated by polyglutamine repeat size, huntingtin expression levels, and protein length. J. Neurosci. 22 (2002), 3473–3483.
119. 119 Hottinger, A.F., Azzouz, M., Déglon, N., Aebischer, P., Zurn, A.D., Complete and long-term rescue of lesioned adult motoneurons by lentiviral-mediated expression of glial cell line-derived neurotrophic factor in the facial nucleus. J. Neurosci. 20 (2000), 5587–5593.
120. 120 Amendola, M., Passerini, L., Pucci, F., Gentner, B., Bacchetta, R., Naldini, L., Regulated and multiple miRNA and siRNA delivery into primary cells by a lentiviral platform. Mol. Ther. 17 (2009), 1039–1052.
121. 121 Makeyev, A.V., Chkheidze, A.N., Liebhaber, S.A., A set of highly conserved RNA-binding proteins, alphaCP-1 and alphaCP-2, implicated in mRNA stabilization, are coexpressed from an intronless gene and its intron-containing paralog. J. Biol. Chem. 274 (1999), 24849–24857.