Antisense oligonucleotides: The next frontier for treatment of neurological disorders

Nature Reviews Neurology

Volumn 14, Issue 1, 2018, Pages 9-22

  Rinaldi, Carlo ^a   Wood, Matthew J A ^a  

^a UNIVERSITY OF OXFORD   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

ANTISENSE OLIGONUCLEOTIDE; BALIFORSEN; BMN 044; BMN 045; DRISAPERSEN; ETEPLIRSEN; IONIS HTTRRX; IONIS SOD1RX; IONIS TTRRX; ISIS SMNRX; ISIS SOD1RX; MORPHOLINO OLIGONUCLEOTIDE; NUSINERSEN; PEPTIDE NUCLEIC ACID; PHOSPHOROTHIOIC ACID; SRP 4045; SRP 4053; SURVIVAL MOTOR NEURON PROTEIN 2; UNCLASSIFIED DRUG; NUCLEOTIDE;

AMYOTROPHIC LATERAL SCLEROSIS; ANTISENSE THERAPY; BINDING AFFINITY; C9ORF72 GENE; CHEMICAL MODIFICATION; DEGENERATIVE DISEASE; DRUG APPROVAL; DRUG BINDING; DRUG DELIVERY SYSTEM; DRUG DESIGN; DRUG HALF LIFE; DRUG MECHANISM; DRUG SAFETY; DRUG SELECTIVITY; DRUG STABILITY; DRUG STRUCTURE; DRUG TARGETING; DRUG TRANSPORT; DUCHENNE MUSCULAR DYSTROPHY; FAMILIAL AMYLOID POLYNEUROPATHY; GENE; GENE MUTATION; GENE SILENCING; GENE TARGETING; HUMAN; HUNTINGTON CHOREA; INTRACELLULAR TRANSPORT; MULTIPLE SCLEROSIS; MYOTONIC DYSTROPHY; NEUROLOGIC DISEASE; NONHUMAN; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN RNA BINDING; REVIEW; RNA SPLICING; SMN2 GENE; SOD1 GENE; SPINAL MUSCULAR ATROPHY; TAUOPATHY; TRANSGENE;

HUMANS; NERVOUS SYSTEM DISEASES; OLIGONUCLEOTIDES, ANTISENSE; THIONUCLEOTIDES;

EID: 85039152289     PISSN: 17594758     EISSN: 17594766     Source Type: Journal    
DOI: 10.1038/nrneurol.2017.148     Document Type: Review

References (230)

1. Stephenson, M. L. & Zamecnik, P. C. Inhibition of Rous sarcoma viral RNA translation by a specific oligodeoxyribonucleotide. Proc. Natl Acad. Sci. USA 75, 285-288 (1978).
2. Muntoni, F. & Wood, M. J. A. Targeting RNA to treat neuromuscular disease. Nat. Rev. Drug Discov. 10, 621-637 (2011).
3. Opalinska, J. B. & Gewirtz, A. M. Nucleic-acid therapeutics: basic principles and recent applications. Nat. Rev. Drug Discov. 1, 503-514 (2002).
4. Juliano, R. L. The delivery of therapeutic oligonucleotides. Nucleic Acids Res. 44, 6518-6548 (2016).
5. Dias, N. & Stein, C. A. Antisense oligonucleotides: basic concepts and mechanisms. Mol. Cancer Ther. 1, 347-355 (2002).
6. Eder, P. S., DeVine, R. J., Dagle, J. M. & Walder, J. A. Substrate specificity and kinetics of degradation of antisense oligonucleotides by a 3' exonuclease in plasma. Antisense Res. Dev. 1, 141-151 (1991).
7. De Clercq, E., Eckstein, E. & Merigan, T. C. Interferon induction increased through chemical modification of a synthetic polyribonucleotide. Science 165, 1137-1139 (1969).
8. Rifai, A., Brysch, W., Fadden, K., Clark, J. & Schlingensiepen, K. H. Clearance kinetics, biodistribution, and organ saturability of phosphorothioate oligodeoxynucleotides in mice. Am. J. Pathol. 149, 717-725 (1996).
9. Watanabe, T. A., Geary, R. S. & Levin, A. A. Plasma protein binding of an antisense oligonucleotide targeting human ICAM-1 (ISIS 2302). Oligonucleotides 16, 169-180 (2006).
10. Wu, H. et al. Determination of the role of the human RNase H1 in the pharmacology of DNA-like antisense drugs. J. Biol. Chem. 279, 17181-17189 (2004).
11. Freier, S. M. & Altmann, K. H. The ups and downs of nucleic acid duplex stability: structure-stability studies on chemically-modified DNA:RNA duplexes. Nucleic Acids Res. 25, 4429-4443 (1997).
12. Lubini, P., Zürcher, W. & Egli, M. Stabilizing effects of the RNA 2'-substituent: crystal structure of an oligodeoxynucleotide duplex containing 2'-O-methylated adenosines. Chem. Biol. 1, 39-45 (1994).
13. McKay, R. A. et al. Characterization of a potent and specific class of antisense oligonucleotide inhibitor of human protein kinase C-alpha expression. J. Biol. Chem. 274, 1715-1722 (1999).
14. Geary, R. S., Yu, R. Z. & Levin, A. A. Pharmacokinetics of phosphorothioate antisense oligodeoxynucleotides. Curr. Opin. Investig. Drugs 2, 562-573 (2001).
15. Hamm, S. et al. Alternating 2'-O-ribose methylation is a universal approach for generating non-stimulatory siRNA by acting as TLR7 antagonist. Immunobiology 215, 559-569 (2010).
16. Summerton, J. et al. Morpholino and phosphorothioate antisense oligomers compared in cell-free and in-cell systems. Antisense Nucleic Acid Drug Dev. 7, 63-70 (1997).
17. Hudziak, R. M. et al. Resistance of morpholino phosphorodiamidate oligomers to enzymatic degradation. Antisense Nucleic Acid Drug Dev. 6, 267-272 (1996).
18. Geary, R. S. Antisense oligonucleotide pharmacokinetics and metabolism. Expert Opin. Drug Metab. Toxicol. 5, 381-391 (2009).
19. Yu, R. Z., Grundy, J. S. & Geary, R. S. Clinical pharmacokinetics of second generation antisense oligonucleotides. Expert Opin. Drug Metab. Toxicol. 9, 169-182 (2013).
20. Crooke, S. T. & Geary, R. S. Clinical pharmacological properties of mipomersen (Kynamro), a second generation antisense inhibitor of apolipoprotein B. Br. J. Clin. Pharmacol. 76, 269-276 (2013).
21. Levin, A. A., Levine, M. S., Rubesin, S. E. & Laufer, I. An 8-year review of barium studies in the diagnosis of gastroparesis. Clin. Radiol. 63, 407-414 (2008).
22. Amantana, A. & Iversen, P. L. Pharmacokinetics and biodistribution of phosphorodiamidate morpholino antisense oligomers. Curr. Opin. Pharmacol. 5, 550-555 (2005).
23. Thompson, J. D. et al. Toxicological and pharmacokinetic properties of chemically modified siRNAs targeting p53 RNA following intravenous administration. Nucleic Acid Ther. 22, 255-264 (2012).
24. Yu, R. Z. et al. Cross-species comparison of in vivo PK/PD relationships for second-generation antisense oligonucleotides targeting apolipoprotein B-100. Biochem. Pharmacol. 77, 910-919 (2009).
25. Zhang, H. et al. Reduction of liver Fas expression by an antisense oligonucleotide protects mice from fulminant hepatitis. Nat. Biotechnol. 18, 862-867 (2000).
26. Altmann, K. H. et al. Second-generation antisense oligonucleotides: structure-activity relationships and the design of improved signal-transduction inhibitors. Biochem. Soc. Trans. 24, 630-637 (1996).
27. Hung, G. et al. Characterization of target mRNA reduction through in situ RNA hybridization in multiple organ systems following systemic antisense treatment in animals. Nucleic Acid Ther. 23, 369-378 (2013).
28. Phillips, J. A. et al. Pharmacokinetics, metabolism, and elimination of a 20-mer phosphorothioate oligodeoxynucleotide (CGP 69846A) after intravenous and subcutaneous administration. Biochem. Pharmacol. 54, 657-668 (1997).
29. Smith, R. A. et al. Antisense oligonucleotide therapy for neurodegenerative disease. J. Clin. Invest. 116, 2290-2296 (2006).
30. Kordasiewicz, H. B. et al. Sustained therapeutic reversal of Huntington's Disease by transient repression of Huntingtin synthesis. Neuron 74, 1031-1044 (2012).
31. Passini, M. A. et al. Antisense oligonucleotides delivered to the mouse CNS ameliorate symptoms of severe spinal muscular atrophy. Sci. Transl Med. 3, 72ra18 (2011).
32. Rigo, F. et al. Pharmacology of a central nervous system delivered 2'-O-methoxyethyl-modified survival of motor neuron splicing oligonucleotide in mice and nonhuman primates. J. Pharmacol. Exp. Ther. 350, 46-55 (2014).
33. Southwell, A. L., Skotte, N. H., Bennett, C. F. & Hayden, M. R. Antisense oligonucleotide therapeutics for inherited neurodegenerative diseases. Trends Mol. Med. 18, 634-643 (2012).
34. Finkel, R. S. et al. Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study. Lancet 388, 3017-3026 (2016).
35. Miller, T. M. et al. An antisense oligonucleotide against SOD1 delivered intrathecally for patients with SOD1 familial amyotrophic lateral sclerosis: a phase 1, randomised, first-in-man study. Lancet Neurol. 12, 435-442 (2013).
36. Ostergaard, M. E. et al. Rational design of antisense oligonucleotides targeting single nucleotide polymorphisms for potent and allele selective suppression of mutant Huntingtin in the CNS. Nucleic Acids Res. 41, 9634-9650 (2013).
37. Chiriboga, C. A. et al. Results from a phase 1 study of nusinersen (ISIS-SMNRx) in children with spinal muscular atrophy. Neurology 86, 890-897 (2016).
38. Alter, J. et al. Systemic delivery of morpholino oligonucleotide restores dystrophin expression bodywide and improves dystrophic pathology. Nat. Med. 12, 175-177 (2006).
39. Benimetskaya, L. et al. Mac-1 (CD11b/CD18) is an oligodeoxynucleotide-binding protein. Nat. Med. 3, 414-420 (1997).
40. Butler, M., Stecker, K. & Bennett, C. F. Cellular distribution of phosphorothioate oligodeoxynucleotides in normal rodent tissues. Lab. Invest. 77, 379-388 (1997).
41. Robbins, M., Judge, A. & MacLachlan, I. siRNA and innate immunity. Oligonucleotides 19, 89-102 (2009).
42. Kawai, T. & Akira, S. Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity 34, 637-650 (2011).
43. Kortylewski, M. et al. In vivo delivery of siRNA to immune cells by conjugation to a TLR9 agonist enhances antitumor immune responses. Nat. Biotechnol. 27, 925-932 (2009).
44. Lorenz, P., Misteli, T., Baker, B. F., Bennett, C. F. & Spector, D. L. Nucleocytoplasmic shuttling: a novel in vivo property of antisense phosphorothioate oligodeoxynucleotides. Nucleic Acids Res. 28, 582-592 (2000).
45. Hartig, R., Shoeman, R. L., Janetzko, A., Grüb, S. & Traub, P. Active nuclear import of single-stranded oligonucleotides and their complexes with non-karyophilic macromolecules. Biol. Cell 90, 407-426 (1998).
46. Varkouhi, A. K., Scholte, M., Storm, G. & Haisma, H. J. Endosomal escape pathways for delivery of biologicals. J. Control. Release 151, 220-228 (2011).
47. Juliano, R. L., Ming, X. & Nakagawa, O. Cellular uptake and intracellular trafficking of antisense and siRNA oligonucleotides. Bioconjug. Chem. 23, 147-157 (2012).
48. Juliano, R. L. & Carver, K. Cellular uptake and intracellular trafficking of oligonucleotides. Adv. Drug Deliv. Rev. 87, 35-45 (2015).
49. Wagenaar, T. R. et al. Identification of the endosomal sorting complex required for transport-I (ESCRT-I) as an important modulator of anti-miR uptake by cancer cells. Nucleic Acids Res. 43, 1204-1215 (2015).
50. Tangsangasaksri, M. et al. siRNA-loaded polyion complex micelle decorated with charge-conversional polymer tuned to undergo stepwise response to intra-tumoral and intra-endosomal pHs for exerting enhanced RNAi efficacy. Biomacromolecules 17, 246-255 (2016).
51. Yang, B. et al. High-throughput screening identifies small molecules that enhance the pharmacological effects of oligonucleotides. Nucleic Acids Res. 43, 1987-1996 (2015).
52. Majorek, K. A. et al. The RNase H-like superfamily: new members, comparative structural analysis and evolutionary classification. Nucleic Acids Res. 42, 4160-4179 (2014).
53. Lima, W. F., De Hoyos, C. L., Liang, X. & Crooke, S. T. RNA cleavage products generated by antisense oligonucleotides and siRNAs are processed by the RNA surveillance machinery. Nucleic Acids Res. 44, 3351-3363 (2016).
54. Deleavey, G. F. & Damha, M. J. Designing chemically modified oligonucleotides for targeted gene silencing. Chem. Biol. 19, 937-954 (2012).
55. Monia, B. P. et al. Evaluation of 2'-modified oligonucleotides containing 2'-deoxy gaps as antisense inhibitors of gene expression. J. Biol. Chem. 268, 14514-14522 (1993).
56. Wu, H., Lima, W. F. & Crooke, S. T. Properties of cloned and expressed human RNase H1. J. Biol. Chem. 274, 28270-28278 (1999).
57. Breaker, R. R. & Joyce, G. F. A. DNA enzyme that cleaves RNA. Chem. Biol. 1, 223-229 (1994).
58. Cech, T. R. & Uhlenbeck, O. C. Hammerhead nailed down. Nature 372, 39-40 (1994).
59. Baker, B. F. et al. 2'-O-(2-Methoxy)ethyl-modified anti-intercellular adhesion molecule 1 (ICAM-1) oligonucleotides selectively increase the ICAM-1 mRNA level and inhibit formation of the ICAM-1 translation initiation complex in human umbilical vein endothelial cells. J. Biol. Chem. 272, 11994-12000 (1997).
60. Evers, M. M., Toonen, L. J. A. & van Roon- Mom, W. M. C. Antisense oligonucleotides in therapy for neurodegenerative disorders. Adv. Drug Deliv. Rev. 87, 90-103 (2015).
61. Havens, M. A. & Hastings, M. L. SURVEY AND SUMMARY Splice-switching antisense oligonucleotides as therapeutic drugs. Nucleic Acids Res. 44, 6549-6563 (2016).
62. US Food and Drug Administration. FDA approves first drug for spinal muscular atrophy. US Food and Drug Administration https://www.fda.gov/newsevents/ newsroom/pressannouncements/ucm534611.htm (2016).
63. Vickers, T. A., Wyatt, J. R., Burckin, T., Bennett, C. F. & Freier, S. M. Fully modified 2' MOE oligonucleotides redirect polyadenylation. Nucleic Acids Res. 29, 1293-1299 (2001).
64. Dominski, Z. & Kole, R. Restoration of correct splicing in thalassemic pre-mRNA by antisense oligonucleotides. Proc. Natl Acad. Sci. USA 90, 8673-8677 (1993).
65. Mah, J. K. et al. A systematic review and meta-analysis on the epidemiology of Duchenne and Becker muscular dystrophy. Neuromuscul. Disord. 24, 482-491 (2014).
66. Judge, L. M., Haraguchiln, M. & Chamberlain, J. S. Dissecting the signaling and mechanical functions of the dystrophin-glycoprotein complex. J. Cell Sci. 119, 1537-1546 (2006).
67. Parker, A. E. et al. Analysis of an adult Duchenne muscular dystrophy population. QJM 98, 729-736 (2005).
68. Guiraud, S. et al. The pathogenesis and therapy of muscular dystrophies. Annu. Rev. Genomics Hum. Genet. 16, 281-308 (2015).
69. Davies, K. E. & Nowak, K. J. Molecular mechanisms of muscular dystrophies: old and new players. Nat. Rev. Mol. Cell Biol. 7, 762-773 (2006).
70. Hoffman, E. P., Brown, R. H. & Kunkel, L. M. Dystrophin: the protein product of the Duchenne muscular dystrophy locus. Cell 51, 919-928 (1987).
71. Bladen, C. L. et al. The TREAT-NMD DMD global database: analysis of more than 7, 000 Duchenne muscular dystrophy mutations. Hum. Mutat. 36, 395-402 (2015).
72. Dunckley, M. G., Manoharan, M., Villiet, P., Eperon, I. C. & Dickson, G. Modification of splicing in the dystrophin gene in cultured Mdx muscle cells by antisense oligoribonucleotides. Hum. Mol. Genet. 7, 1083-1090 (1998).
73. Pramono, Z. A. et al. Induction of exon skipping of the dystrophin transcript in lymphoblastoid cells by transfecting an antisense oligodeoxynucleotide complementary to an exon recognition sequence. Biochem. Biophys. Res. Commun. 226, 445-449 (1996).
74. Takeshima, Y., Nishio, H., Sakamoto, H., Nakamura, H. & Matsuo, M. Modulation of in vitro splicing of the upstream intron by modifying an intra-exon sequence which is deleted from the dystrophin gene in dystrophin Kobe. J. Clin. Invest. 95, 515-520 (1995).
75. Aartsma-Rus, A. et al. Targeted exon skipping as a potential gene correction therapy for Duchenne muscular dystrophy. Neuromuscul. Disord. 12 (Suppl. 1), S71-S77 (2002).
76. Aartsma-Rus, A. et al. Comparative analysis of antisense oligonucleotide analogs for targeted DMD exon 46 skipping in muscle cells. Gene Ther. 11, 1391-1398 (2004).
77. Popplewell, L. J. et al. Comparative analysis of antisense oligonucleotide sequences targeting exon 53 of the human DMD gene: Implications for future clinical trials. Neuromuscul. Disord. 20, 102-110 (2010).
78. Popplewell, L. J., Trollet, C., Dickson, G. & Graham, I. R. Design of phosphorodiamidate morpholino oligomers (PMOs) for the induction of exon skipping of the human DMD gene. Mol. Ther. 17, 554-561 (2009).
79. van Deutekom, J. C. et al. Antisense-induced exon skipping restores dystrophin expression in DMD patient derived muscle cells. Hum. Mol. Genet. 10, 1547-1554 (2001).
80. van Deutekom, J. C. T. & van Ommen, G.-J. B. Advances in Duchenne muscular dystrophy gene therapy. Nat. Rev. Genet. 4, 774-783 (2003).
81. Yokota, T., Duddy, W. & Partridge, T. Optimizing exon skipping therapies for DMD. Acta Myol. 26, 179-184 (2007).
82. Lu, Q. L. et al. Systemic delivery of antisense oligoribonucleotide restores dystrophin expression in body-wide skeletal muscles. Proc. Natl Acad. Sci. USA 102, 198-203 (2005).
83. Heemskerk, H. et al. Preclinical PK and PD studies on 2'-O-methyl-phosphorothioate RNA antisense oligonucleotides in the mdx mouse model. Mol. Ther. 18, 1210-1217 (2010).
84. Heemskerk, H. A. et al. In vivo comparison of 2'-O-methyl phosphorothioate and morpholino antisense oligonucleotides for Duchenne muscular dystrophy exon skipping. J. Gene Med. 11, 257-266 (2009).
85. Yokota, T., Hoffman, E. & Takeda, S. Antisense oligo-mediated multiple exon skipping in a dog model of duchenne muscular dystrophy. Methods Mol. Biol. 709, 299-312 (2011).
86. Malerba, A., Boldrin, L. & Dickson, G. Long-term systemic administration of unconjugated morpholino oligomers for therapeutic expression of dystrophin by exon skipping in skeletal muscle: implications for cardiac muscle integrity. Nucleic Acid. Ther. 21, 293-298 (2011).
87. Townsend, D., Yasuda, S., Li, S., Chamberlain, J. S. & Metzger, J. M. Emergent dilated cardiomyopathy caused by targeted repair of dystrophic skeletal muscle. Mol. Ther. 16, 832-835 (2008).
88. Cirak, S. et al. Exon skipping and dystrophin restoration in patients with Duchenne muscular dystrophy after systemic phosphorodiamidate morpholino oligomer treatment: an open-label, phase 2, dose-escalation study. Lancet 378, 595-605 (2011).
89. Mendell, J. R. et al. Eteplirsen for the treatment of Duchenne muscular dystrophy. Ann. Neurol. 74, 637-647 (2013).
90. Sarepta Therapeutics, Inc. PCNSD Advisory Committee Meeting Briefing Document. U.S. Food and Drug Administration https://www.fda.gov/downloads/ advisorycommittees/committeesmeetingmaterials/ drugs/peripheralandcentralnervoussystem drugsadvisorycommittee/ucm497064.pdf (2017).
91. US Food and Drug Administration. FDA grants accelerated approval to first drug for Duchenne muscular dystrophy. US Food and Drug Administration https://www.fda.gov/NewsEvents/Newsroom/ PressAnnouncements/ucm521263.htm (2016).
92. Kesselheim, A. S. & Avorn, J. Approving a problematic muscular dystrophy drug. JAMA 316, 2357 (2016).
93. Pearson, S., Jia, H. & Kandachi, K. China approves first gene therapy. Nat. Biotechnol. 22, 3-4 (2004).
94. Hoyng, S. A. et al. Gene therapy and peripheral nerve repair: a perspective. Front. Mol. Neurosci. 8, 32 (2015).
95. Leader, B., Baca, Q. J. & Golan, D. E. Protein therapeutics: a summary and pharmacological classification. Nat. Rev. Drug Discov. 7, 21-39 (2008).
96. Liang, X. et al. Translation efficiency of mRNAs is increased by antisense oligonucleotides targeting upstream open reading frames. Nat. Biotechnol. 34, 875-880 (2016).
97. Calvo, S. E., Pagliarini, D. J. & Mootha, V. K. Upstream open reading frames cause widespread reduction of protein expression and are polymorphic among humans. Proc. Natl Acad. Sci. USA 106, 7507-7512 (2009).
98. Lee, S. et al. Global mapping of translation initiation sites in mammalian cells at single-nucleotide resolution. Proc. Natl Acad. Sci. USA 109, E2424-E2432 (2012).
99. Orr, H. T. & Zoghbi, H. Y. Trinucleotide repeat disorders. Annu. Rev. Neurosci. 30, 575-621 (2007).
100. Davies, S. W. et al. Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation. Cell 90, 537-548 (1997).
101. Seidel, K. et al. Brain pathology of spinocerebellar ataxias. Acta Neuropathol. 124, 1-21 (2012).
102. Hu, J. et al. Allele-specific silencing of mutant huntingtin and ataxin-3 genes by targeting expanded CAG repeats in mRNAs. Nat. Biotechnol. 27, 478-484 (2009).
103. Hu, J., Liu, J. & Corey, D. R. Allele-selective inhibition of Huntingtin expression by switching to an miRNA-like RNAi mechanism. Chem. Biol. 17, 1183-1188 (2010).
104. Gagnon, K. T. et al. Allele-selective inhibition of mutant Huntingtin expression with antisense oligonucleotides targeting the expanded CAG repeat. Biochemistry 49, 10166-10178 (2010).
105. Sun, X. et al. Phosphorodiamidate morpholino oligomers suppress mutant huntingtin expression and attenuate neurotoxicity. Hum. Mol. Genet. 23, 6302-6317 (2014).
106. van Bilsen, P. H. J. et al. Identification and allele-specific silencing of the mutant huntingtin allele in Huntington's disease patient-derived fibroblasts. Hum. Gene Ther. 19, 710-718 (2008).
107. Lombardi, M. S. et al. A majority of Huntington's disease patients may be treatable by individualized allele-specific RNA interference. Exp. Neurol. 217, 312-319 (2009).
108. Carroll, J. B. et al. Potent and selective antisense oligonucleotides targeting single-nucleotide polymorphisms in the Huntington disease gene/ allele-specific silencing of mutant huntingtin. Mol. Ther. 19, 2178-2185 (2011).
109. Warby, S. C. et al. CAG expansion in the Huntington disease gene is associated with a specific and targetable predisposing haplogroup. Am. J. Hum. Genet. 84, 351-366 (2009).
110. Pfister, E. L. et al. Five siRNAs targeting three SNPs may provide therapy for three-quarters of Huntington's disease patients. Curr. Biol. 19, 774-778 (2009).
111. Rosen, D. R. et al. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362, 59-62 (1993).
112. Winer, L. et al. SOD1 in cerebral spinal fluid as a pharmacodynamic marker for antisense oligonucleotide therapy. JAMA Neurol. 70, 201-207 (2013).
113. Crisp, M. J. et al. In vivo kinetic approach reveals slow SOD1 turnover in the CNS. J. Clin. Invest. 125, 2772-2780 (2015).
114. Andreadis, A. Misregulation of tau alternative splicing in neurodegeneration and dementia. Prog. Mol. Subcell. Biol. 44, 89-107 (2006).
115. Lee, G., Cowan, N. & Kirschner, M. The primary structure and heterogeneity of tau protein from mouse brain. Science 239, 285-288 (1988).
116. Lindwall, G. & Cole, R. D. Phosphorylation affects the ability of tau protein to promote microtubule assembly. J. Biol. Chem. 259, 5301-5305 (1984).
117. Alonso, A. C., Zaidi, T., Grundke-Iqbal, I. & Iqbal, K. Role of abnormally phosphorylated tau in the breakdown of microtubules in Alzheimer disease. Proc. Natl Acad. Sci. USA 91, 5562-5566 (1994).
118. Grundke-Iqbal, I. et al. Abnormal phosphorylation of the microtubule-associated protein τ (tau) in Alzheimer cytoskeletal pathology. Proc. Natl Acad. Sci. USA 83, 4913-4917 (1986).
119. Iqbal, K. et al. Defective brain microtubule assembly in Alzheimer's disease. Lancet 2, 421-426 (1986).
120. Braak, H. & Braak, E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 82, 239-259 (1991).
121. Tomlinson, B. E., Blessed, G. & Roth, M. Observations on the brains of demented old people. J. Neurol. Sci. 11, 205-242 (1970).
122. Alafuzoff, I., Iqbal, K., Friden, H., Adolfsson, R. & Winblad, B. Histopathological criteria for progressive dementia disorders: clinical-pathological correlation and classification by multivariate data analysis. Acta Neuropathol. 74, 209-225 (1987).
123. Arriagada, P. V., Growdon, J. H., Hedley-Whyte, E. T. & Hyman, B. T. Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer's disease. Neurology 42, 631-639 (1992).
124. Hyman, B. T., Van Hoesen, G. W., Damasio, A. R. & Barnes, C. L. Alzheimer's disease: cell-specific pathology isolates the hippocampal formation. Science 225, 1168-1170 (1984).
125. Lei, P. et al. Tau deficiency induces parkinsonism with dementia by impairing APP-mediated iron export. Nat. Med. 18, 291-295 (2012).
126. Morris, M. et al. Age-appropriate cognition and subtle dopamine-independent motor deficits in aged Tau knockout mice. Neurobiol. Aging 34, 1523-1529 (2013).
127. Li, Z., Hall, A. M., Kelinske, M. & Roberson, E. D. Seizure resistance without parkinsonism in aged mice after tau reduction. Neurobiol. Aging 35, 2617-2624 (2014).
128. Roberson, E. D. et al. Reducing endogenous tau ameliorates amyloid β-induced deficits in an Alzheimer's disease mouse model. Science 316, 750-754 (2007).
129. van Hummel, A. et al. No overt deficits in aged tau-deficient C57Bl/6.Mapttm1(EGFP)Kit GFP knockin mice. PLoS ONE 11, e0163236 (2016).
130. DeVos, S. L. & Miller, T. M. Antisense oligonucleotides: treating neurodegeneration at the level of RNA. Neurotherapeutics 10, 486-497 (2013).
131. Sud, R., Geller, E. T. & Schellenberg, G. D. Antisense-mediated exon skipping decreases tau protein expression: a potential therapy for tauopathies. Mol. Ther. Nucleic Acids 3, e180 (2014).
132. Yoshiyama, Y. et al. Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron 53, 337-351 (2007).
133. DeVos, S. L. et al. Tau reduction prevents neuronal loss and reverses pathological tau deposition and seeding in mice with tauopathy. Sci. Transl Med. 9, eaag0481 (2017).
134. Schoch, K. M. et al. Increased 4R-tau induces pathological changes in a human-tau mouse model. Neuron 90, 941-947 (2016).
135. Jiang, H., Mankodi, A., Swanson, M. S., Moxley, R. T. & Thornton, C. A. Myotonic dystrophy type 1 is associated with nuclear foci of mutant RNA, sequestration of muscleblind proteins and deregulated alternative splicing in neurons. Hum. Mol. Genet. 13, 3079-3088 (2004).
136. Mahadevan, M. S. et al. Reversible model of RNA toxicity and cardiac conduction defects in myotonic dystrophy. Nat. Genet. 38, 1066-1070 (2006).
137. Ranum, L. P. W. & Cooper, T. A. RNA-mediated neuromuscular disorders. Annu. Rev. Neurosci. 29, 259-277 (2006).
138. Orengo, J. P. et al. Expanded CTG repeats within the DMPK 3' UTR causes severe skeletal muscle wasting in an inducible mouse model for myotonic dystrophy. Proc. Natl Acad. Sci. USA 105, 2646-2651 (2008).
139. Yadava, R. S. et al. RNA toxicity in myotonic muscular dystrophy induces NKX2-5 expression. Nat. Genet. 40, 61-68 (2008).
140. Day, J. W. et al. Myotonic dystrophy type 2: molecular, diagnostic and clinical spectrum. Neurology 60, 657-664 (2003).
141. Liquori, C. L. et al. Myotonic dystrophy Type 2: human founder haplotype and evolutionary conservation of the repeat tract. Am. J. Hum. Genet. 73, 849-862 (2003).
142. Margolis, J. M., Schoser, B. G., Moseley, M. L., Day, J. W. & Ranum, L. P. W. DM2 intronic expansions: evidence for CCUG accumulation without flanking sequence or effects on ZNF9 mRNA processing or protein expression. Hum. Mol. Genet. 15, 1808-1815 (2006).
143. Lee, J. E. & Cooper, T. A. Pathogenic mechanisms of myotonic dystrophy. Biochem. Soc. Trans. 37, 1281-1286 (2009).
144. Napierała, M. & Krzyzosiak, W. J. CUG repeats present in myotonin kinase RNA form metastable "slippery" hairpins. J. Biol. Chem. 272, 31079-31085 (1997).
145. Kuyumcu-Martinez, N. M. & Cooper, T. A. Misregulation of alternative splicing causes pathogenesis in myotonic dystrophy. Prog. Mol. Subcell. Biol. 44, 133-159 (2006).
146. Cardani, R., Mancinelli, E., Rotondo, G., Sansone, V. & Meola, G. Muscleblind-like protein 1 nuclear sequestration is a molecular pathology marker of DM1 and DM2. Eur. J. Histochem. 50, 177-182 (2006).
147. Fardaei, M., Larkin, K., Brook, J. D. & Hamshere, M. G. In vivo co-localisation of MBNL protein with DMPK expanded-repeat transcripts. Nucleic Acids Res. 29, 2766-2771 (2001).
148. Fardaei, M. et al. Three proteins, MBNL, MBLL and MBXL, co-localize in vivo with nuclear foci of expanded-repeat transcripts in DM1 and DM2 cells. Hum. Mol. Genet. 11, 805-814 (2002).
149. Ward, A. J., Rimer, M., Killian, J. M., Dowling, J. J. & Cooper, T. A. CUGBP1 overexpression in mouse skeletal muscle reproduces features of myotonic dystrophy type 1. Hum. Mol. Genet. 19, 3614-3622 (2010).
150. Yuan, Y. et al. Muscleblind-like 1 interacts with RNA hairpins in splicing target and pathogenic RNAs. Nucleic Acids Res. 35, 5474-5486 (2007).
151. Koshelev, M., Sarma, S., Price, R. E., Wehrens, X. H. T. & Cooper, T. A. Heart-specific overexpression of CUGBP1 reproduces functional and molecular abnormalities of myotonic dystrophy type 1. Hum. Mol. Genet. 19, 1066-1075 (2010).
152. Du, H. et al. Aberrant alternative splicing and extracellular matrix gene expression in mouse models of myotonic dystrophy. Nat. Struct. Mol. Biol. 17, 187-193 (2010).
153. Wheeler, T. M. et al. Reversal of RNA dominance by displacement of protein sequestered on triplet repeat RNA. Science 325, 336-339 (2009).
154. Furling, D. et al. Viral vector producing antisense RNA restores myotonic dystrophy myoblast functions. Gene Ther. 10, 795-802 (2003).
155. Mulders, S. A. M. et al. Triplet-repeat oligonucleotide-mediated reversal of RNA toxicity in myotonic dystrophy. Proc. Natl Acad. Sci. USA 106, 13915-13920 (2009).
156. Majounie, E. et al. Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study. Lancet Neurol. 11, 323-330 (2012).
157. DeJesus-Hernandez, M. et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 72, 245-256 (2011).
158. Renton, A. E. et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 72, 257-268 (2011).
159. Belzil, V. V., Gendron, T. F. & Petrucelli, L. RNA-mediated toxicity in neurodegenerative disease. Mol. Cell. Neurosci. 56, 406-419 (2013).
160. Gijselinck, I. et al. A C9orf72 promoter repeat expansion in a Flanders-Belgian cohort with disorders of the frontotemporal lobar degeneration-amyotrophic lateral sclerosis spectrum: a gene identification study. Lancet Neurol. 11, 54-65 (2012).
161. Liu, E. Y. et al. C9orf72 hypermethylation protects against repeat expansion-associated pathology in ALS/FTD. Acta Neuropathol. 128, 525-541 (2014).
162. Xi, Z. et al. Hypermethylation of the CpG island near the G4C2 repeat in ALS with a C9orf72 expansion. Am. J. Hum. Genet. 92, 981-989 (2013).
163. Xi, Z. et al. The C9orf72 repeat expansion itself is methylated in ALS and FTLD patients. Acta Neuropathol. 129, 715-727 (2015).
164. Gendron, T. F., Belzil, V. V., Zhang, Y.-J. & Petrucelli, L. Mechanisms of toxicity in C9FTLD/ALS. Acta Neuropathol. 127, 359-376 (2014).
165. Ling, S.-C., Polymenidou, M. & Cleveland, D. W. Converging mechanisms in ALS and FTD: disrupted RNA and protein homeostasis. Neuron 79, 416-438 (2013).
166. Jiang, J. et al. Gain of toxicity from ALS/FTD-linked repeat expansions in C9ORF72 is alleviated by antisense oligonucleotides targeting GGGGCC-containing RNAs. Neuron 90, 535-550 (2016).
167. Zu, T. et al. Non-ATG-initiated translation directed by microsatellite expansions. Proc. Natl Acad. Sci. USA 108, 260-265 (2011).
168. Cleary, J. D. & Ranum, L. P. W. Repeat-associated non-ATG (RAN) translation in neurological disease. Hum. Mol. Genet. 22, R45-R51 (2013).
169. Freibaum, B. D. & Taylor, J. P. The role of dipeptide repeats in C9ORF72-related ALS-FTD. Front. Mol. Neurosci. 10, 35 (2017).
170. Lagier-Tourenne, C. et al. Targeted degradation of sense and antisense C9orf72 RNA foci as therapy for ALS and frontotemporal degeneration. Proc. Natl Acad. Sci. USA 110, E4530-E4539 (2013).
171. Donnelly, C. J. et al. RNA toxicity from the ALS/FTD C9ORF72 expansion is mitigated by antisense intervention. Neuron 80, 415-428 (2013).
172. Prior, T. W. & Finanger, E. in GeneReviews® (eds Adam, M. P. et al.) Ch. Spinal Muscular Atrophy (University of Washington, 2000).
173. Brzustowicz, L. M. et al. Genetic mapping of chronic childhood-onset spinal muscular atrophy to chromosome 5q1 1.2-13.3. Nature 344, 540-541 (1990).
174. Burghes, A. H. M. & Beattie, C. E. Spinal muscular atrophy: why do low levels of survival motor neuron protein make motor neurons sick? Nat. Rev. Neurosci. 10, 597-609 (2009).
175. Singh, N. K., Singh, N. N., Androphy, E. J. & Singh, R. N. Splicing of a critical exon of human Survival Motor Neuron is regulated by a unique silencer element located in the last intron. Mol. Cell. Biol. 26, 1333-1346 (2006).
176. Singh, N. N., Howell, M. D., Androphy, E. J. & Singh, R. N. How the discovery of ISS-N1 led to the first medical therapy for spinal muscular atrophy. Gene Ther. 24, 520-526 (2017).
177. Williams, J. H. et al. Oligonucleotide-mediated survival of motor neuron protein expression in CNS improves phenotype in a mouse model of spinal muscular atrophy. J. Neurosci. 29, 7633-7638 (2009).
178. Hua, Y. et al. Antisense correction of SMN2 splicing in the CNS rescues necrosis in a type III SMA mouse model. Genes Dev. 24, 1634-1644 (2010).
179. Hua, Y. et al. Peripheral SMN restoration is essential for long-term rescue of a severe spinal muscular atrophy mouse model. Nature 478, 123-126 (2011).
180. Porensky, P. N. et al. A single administration of morpholino antisense oligomer rescues spinal muscular atrophy in mouse. Hum. Mol. Genet. 21, 1625-1638 (2012).
181. Zhou, H. et al. A novel morpholino oligomer targeting ISS-N1 improves rescue of severe spinal muscular atrophy transgenic mice. Hum. Gene Ther. 24, 331-342 (2013).
182. Boyer, J. G., Ferrier, A. & Kothary, R. More than a bystander: the contributions of intrinsic skeletal muscle defects in motor neuron diseases. Front. Physiol. 4, 356 (2013).
183. Smith, L., Andersen, K. B., Hovgaard, L. & Jaroszewski, J. W. Rational selection of antisense oligonucleotide sequences. Eur. J. Pharm. Sci. 11, 191-198 (2000).
184. Echigoya, Y., Mouly, V., Garcia, L., Yokota, T. & Duddy, W. In silico screening based on predictive algorithms as a design tool for exon skipping oligonucleotides in Duchenne muscular dystrophy. PLoS ONE 10, e0120058 (2015).
185. Goyenvalle, A. et al. Functional correction in mouse models of muscular dystrophy using exon-skipping tricyclo-DNA oligomers. Nat. Med. 21, 270-275 (2015).
186. Iwamoto, N. et al. Control of phosphorothioate stereochemistry substantially increases the efficacy of antisense oligonucleotides. Nat. Biotechnol. 35, 845-851 (2017).
187. Alavijeh, M. S., Chishty, M., Qaiser, M. Z. & Palmer, A. M. Drug metabolism and pharmacokinetics, the blood-brain barrier, and central nervous system drug discovery. NeuroRx 2, 554-571 (2005).
188. Bedi, D. et al. Targeted delivery of siRNA into breast cancer cells via phage fusion proteins. Mol. Pharm. 10, 551-559 (2013).
189. Falzarano, M. S., Passarelli, C. & Ferlini, A. Nanoparticle delivery of antisense oligonucleotides and their application in the exon skipping strategy for Duchenne muscular dystrophy. Nucleic Acid. Ther. 24, 87-100 (2014).
190. Lehto, T., Ezzat, K. & Wood, M. J. A. & EL Andaloussi, S. Peptides for nucleic acid delivery. Adv. Drug Deliv. Rev. 106, 172-182 (2016).
191. Ivanova, G. D. et al. PNA-peptide conjugates as intracellular gene control agents. Nucleic Acids Symp. Ser. 52, 31-32 (2008).
192. Jearawiriyapaisarn, N. et al. Sustained dystrophin expression induced by peptide-conjugated morpholino oligomers in the muscles of mdx mice. Mol. Ther. 16, 1624-1629 (2008).
193. Wu, B. et al. Effective rescue of dystrophin improves cardiac function in dystrophin-deficient mice by a modified morpholino oligomer. Proc. Natl Acad. Sci. USA 105, 14814-14819 (2008).
194. Yin, H. et al. Pip5 transduction peptides direct high efficiency oligonucleotide-mediated dystrophin exon skipping in heart and phenotypic correction in mdx mice. Mol. Ther. 19, 1295-1303 (2011).
195. Hammond, S. M. et al. Systemic peptide-mediated oligonucleotide therapy improves long-term survival in spinal muscular atrophy. Proc. Natl Acad. Sci. USA 113, 10962-10967 (2016).
196. Henry, S. P., Bolte, H., Auletta, C. & Kornbrust, D. J. Evaluation of the toxicity of ISIS 2302, a phosphorothioate oligonucleotide, in a four-week study in cynomolgus monkeys. Toxicology 120, 145-155 (1997).
197. Straarup, E. M. et al. Short locked nucleic acid antisense oligonucleotides potently reduce apolipoprotein B mRNA and serum cholesterol in mice and non-human primates. Nucleic Acids Res. 38, 7100-7111 (2010).
198. Iversen, P. L., Cornish, K. G., Iversen, L. J., Mata, J. E. & Bylund, D. B. Bolus intravenous injection of phosphorothioate oligonucleotides causes hypotension by acting as α1-adrenergic receptor antagonists. Toxicol. Appl. Pharmacol. 160, 289-296 (1999).
199. Lindow, M. et al. Assessing unintended hybridization-induced biological effects of oligonucleotides. Nat. Biotechnol. 30, 920-923 (2012).
200. Goemans, N. M. et al. Systemic administration of PRO051 in Duchenne's muscular dystrophy. N. Engl. J. Med. 364, 1513-1522 (2011).
201. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01128855 (2017).
202. Voit, T. et al. Safety and efficacy of drisapersen for the treatment of Duchenne muscular dystrophy (DEMAND II): an exploratory, randomised, placebo-controlled phase 2 study. Lancet Neurol. 13, 987-996 (2014).
203. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01254019 (2017).
204. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01480245 (2017).
205. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01462292 (2017).
206. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01803412 (2016).
207. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02636686 (2016).
208. Kinali, M., et al. Local restoration of dystrophin expression with the morpholino oligomer AVI-4658 in Duchenne muscular dystrophy: a single-blind, placebo-controlled, dose-escalation, proof-of-concept study. Lancet Neurol. 8, 918-928 (2009).
209. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01540409 (2016).
210. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02255552 (2017).
211. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02286947 (2017).
212. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02420379 (2017).
213. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01037309 (2015).
214. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01826474 (2015).
215. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02500381 (2017).
216. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01494701 (2017).
217. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01703988 (2017).
218. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01780246 (2017).
219. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02052791 (2017).
220. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02193074 (2017).
221. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02292537 (2017).
222. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02386553 (2017).
223. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02462759 (2017).
224. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02594124 (2017).
225. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02865109 (2017).
226. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01737398 (2016).
227. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02519036 (2017).
228. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02623699 (2017).
229. Limmroth, V. et al. CD49d antisense drug ATL1102 reduces disease activity in patients with relapsing-remitting MS. Neurology 83, 1780-1788 (2014).
230. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02312011 (2016).