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Antisense Oligonucleotide-Based Therapies for Diseases Caused by pre-mRNA Processing Defects

  • Frank Rigo
  • Punit P. Seth
  • C. Frank Bennett
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 825)

Abstract

Before a messenger RNA (mRNA) is translated into a protein in the cytoplasm, its pre-mRNA precursor is extensively processed through capping, splicing and polyadenylation in the nucleus. Defects in the processing of pre-mRNAs due to mutations in RNA sequences often cause disease. Traditional small molecules or protein-based therapeutics are not well suited for correcting processing defects by targeting RNA. However, antisense oligonucleotides (ASOs) designed to bind RNA by Watson-Crick base pairing can target most RNA transcripts and have emerged as the ideal therapeutic agents for diseases that are caused by pre-mRNA processing defects. Here we review the diverse ASO-based mechanisms that can be exploited to modulate the expression of RNA. We also discuss how advancements in medicinal chemistry and a deeper understanding of the pharmacokinetic and toxicological properties of ASOs have enabled their use as therapeutic agents. We end by describing how ASOs have been used successfully to treat various pre-mRNA processing diseases in animal models.

Keywords

Antisense oligonucleotide Pre-mRNA processing Splicing RNA binding protein RNase H siRNA Myotonic dystrophy Spinal muscular atrophy Hutchinson-Gilford progeria syndrome Usher syndrome Fukuyama congenital muscular dystrophy 

Notes

Acknowledgements

We apologize to those authors whose work could not be cited due to space limitations. We thank Tracy Reigle for the illustrations.

References

  1. Aartsma-Rus A (2012) Overview on AON design. Methods Mol Biol 867:117–129PubMedGoogle Scholar
  2. Allerson CR, Sioufi N, Jarres R, Prakash TP, Naik N, Berdeja A, Wanders L, Griffey RH, Swayze EE, Bhat B (2005) Fully 2′-modified oligonucleotide duplexes with improved in vitro potency and stability compared to unmodified small interfering RNA. J Med Chem 48:901–904PubMedGoogle Scholar
  3. Allo M, Buggiano V, Fededa JP, Petrillo E, Schor I, de la Mata M, Agirre E, Plass M, Eyras E, Elela SA et al (2009) Control of alternative splicing through siRNA-mediated transcriptional gene silencing. Nat Struct Mol Biol 16:717–724PubMedGoogle Scholar
  4. Anthony K, Gallo JM (2010) Aberrant RNA processing events in neurological disorders. Brain Res 1338:67–77PubMedGoogle Scholar
  5. Araujo Ade Q, Araujo M, Swoboda KJ (2009) Vascular perfusion abnormalities in infants with spinal muscular atrophy. J Pediatr 155:292–294Google Scholar
  6. Arora V, Knapp DC, Smith BL, Statdfield ML, Stein DA, Reddy MT, Weller DD, Iversen PL (2000) c-Myc antisense limits rat liver regeneration and indicates role for c-Myc in regulating cytochrome P-450 3A activity. J Pharmacol Exp Ther 292:921–928PubMedGoogle Scholar
  7. Bachelin M, Hessler G, Kurz G, Hacia JG, Dervan PB, Kessler H (1998) Structure of a stereoregular phosphorothioate DNA/RNA duplex. Nat Struct Biol 5:271–276PubMedGoogle Scholar
  8. Baker BF, Lot SS, Condon TP, Cheng-Flournoy S, Lesnik EA, Sasmor HM, Bennett CF (1997) 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 272:11994–12000PubMedGoogle Scholar
  9. Baker BF, Lot SS, Kringel J, Cheng-Flournoy S, Villiet P, Sasmor HM, Siwkowski AM, Chappell LL, Morrow JR (1999) Oligonucleotide-europium complex conjugate designed to cleave the 5′ cap structure of the ICAM-1 transcript potentiates antisense activity in cells. Nucleic Acids Res 27:1547–1551PubMedCentralPubMedGoogle Scholar
  10. Baker BF, Miraglia L, Hagedorn CH (1992) Modulation of eucaryotic initiation factor-4E binding to 5′-capped oligoribonucleotides by modified anti-sense oligonucleotides. J Biol Chem 267:11495–11499PubMedGoogle Scholar
  11. Baltz AG, Munschauer M, Schwanhausser B, Vasile A, Murakawa Y, Schueler M, Youngs N, Penfold-Brown D, Drew K, Milek M et al (2012) The mRNA-bound proteome and its global occupancy profile on protein-coding transcripts. Mol Cell 46:674–690PubMedGoogle Scholar
  12. Barresi R, Campbell KP (2006) Dystroglycan: from biosynthesis to pathogenesis of human disease. J Cell Sci 119:199–207PubMedGoogle Scholar
  13. Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116: 281–297PubMedGoogle Scholar
  14. Bartel DP (2009) MicroRNAs: target recognition and regulatory functions. Cell 136:215–233PubMedCentralPubMedGoogle Scholar
  15. Batey RT, Rambo RP, Doudna JA (1999) Tertiary Motifs in RNA Structure and Folding. Angewandte Chemie 38:2326–2343PubMedGoogle Scholar
  16. Baughan TD, Dickson A, Osman EY, Lorson CL (2009) Delivery of bifunctional RNAs that target an intronic repressor and increase SMN levels in an animal model of spinal muscular atrophy. Hum Mol Genet 18(9):1600–1611PubMedCentralPubMedGoogle Scholar
  17. Bauman J, Jearawiriyapaisarn N, Kole R (2009) Therapeutic potential of splice-switching oligonucleotides. Oligonucleotides 19(1):1–13PubMedCentralPubMedGoogle Scholar
  18. Baumer D, Lee S, Nicholson G, Davies JL, Parkinson NJ, Murray LM, Gillingwater TH, Ansorge O, Davies KE, Talbot K (2009) Alternative splicing events are a late feature of pathology in a mouse model of spinal muscular atrophy. PLoS Genet 5:e1000773PubMedCentralPubMedGoogle Scholar
  19. Belostotsky D (2009) Exosome complex and pervasive transcription in eukaryotic genomes. Curr Opin Cell Biol 21:352–358PubMedGoogle Scholar
  20. Bennett CF (2007) Pharmacological properties of 2′-O-methoxyethyl-modified oligonucleotides. In: Crooke ST (ed) Antisense drug technology: principles, strategies, and applications. CRC, Boca Raton, FL, pp 273–303Google Scholar
  21. Bennett CF, Chiang MY, Chan H, Grimm S (1993) Use of cationic lipids to enhance the biological activity of antisense oligonucleotides. J Liposome Res 3:85–102Google Scholar
  22. Bennett CF, Swayze EE (2010) RNA targeting therapeutics: molecular mechanisms of antisense oligonucleotides as a therapeutic platform. Annu Rev Pharmacol Toxicol 50:259–293PubMedGoogle Scholar
  23. Bevan AK, Hutchinson KR, Foust KD, Braun L, McGovern VL, Schmelzer L, Ward JG, Petruska JC, Lucchesi PA, Burghes AH et al (2010) Early heart failure in the SMNDelta7 model of spinal muscular atrophy and correction by postnatal scAAV9-SMN delivery. Hum Mol Genet 19:3895–3905PubMedCentralPubMedGoogle Scholar
  24. Bitner-Glindzicz M, Lindley KJ, Rutland P, Blaydon D, Smith VV, Milla PJ, Hussain K, Furth-Lavi J, Cosgrove KE, Shepherd RM et al (2000) A recessive contiguous gene deletion causing infantile hyperinsulinism, enteropathy and deafness identifies the Usher type 1C gene. Nat Genet 26:56–60PubMedGoogle Scholar
  25. Black DL (2003) Mechanisms of alternative pre-messenger RNA splicing. Annu Rev Biochem 72:291–336PubMedGoogle Scholar
  26. Braasch DA, Paroo Z, Constantinescu A, Ren G, Oz OK, Mason RP, Corey DR (2004) Biodistribution of phosphodiester and phosphorothioate siRNA. Bioorg Med Chem Lett 14:1139–1143PubMedGoogle Scholar
  27. Brachet J (1941) La détection histochimique et le microdosage des acides pentosenucléiques (tissus animaux—développement embryonnaire des amphibiens). Enzymologia 10:87–96Google Scholar
  28. Braunschweig U, Gueroussov S, Plocik AM, Graveley BR, Blencowe BJ (2013) Dynamic integration of splicing within gene regulatory pathways. Cell 152:1252–1269PubMedCentralPubMedGoogle Scholar
  29. Breaker RR, Joyce GF (1994) A DNA enzyme that cleaves RNA. Chem Biol 1:223–229PubMedGoogle Scholar
  30. Brook JD, McCurrach ME, Harley HG, Buckler AJ, Church D, Aburatani H, Hunter K, Stanton VP, Thirion JP, Hudson T et al (1992) Molecular basis of myotonic dystrophy: expansion of a trinucleotide (CTG) repeat at the 3′ end of a transcript encoding a protein kinase family member. Cell 68:799–808PubMedGoogle Scholar
  31. Brown-Driver V, Eto T, Lesnik E, Anderson KP, Hanecak RC (1999) Inhibition of translation of hepatitis C virus RNA by 2-modified antisense oligonucleotides. Antisense Nucleic Acid Drug Dev 9:145–154PubMedGoogle Scholar
  32. Bumcrot D, Manoharan M, Koteliansky V, Sah DW (2006) RNAi therapeutics: a potential new class of pharmaceutical drugs. Nat Chem Biol 2:711–719PubMedGoogle Scholar
  33. Burel SA, Han SR, Lee HS, Norris DA, Lee BS, Machemer T, Park SY, Zhou T, He G, Kim Y et al (2013) Preclinical evaluation of the toxicological effects of a novel constrained ethyl modified antisense compound targeting signal transducer and activator of transcription 3 in mice and cynomolgus monkeys. Nucleic Acid Ther 23:213–227PubMedGoogle Scholar
  34. Burel SA, Machemer T, Ragone FL, Kato H, Cauntay P, Greenlee S, Salim A, Gaarde WA, Hung G, Peralta R et al (2012) Unique O-methoxyethyl ribose-DNA chimeric oligonucleotide induces an atypical melanoma differentiation-associated gene 5-dependent induction of type I interferon response. J Pharmacol Exp Ther 342:150–162PubMedGoogle Scholar
  35. Burghes AH, Beattie CE (2009) Spinal muscular atrophy: why do low levels of survival motor neuron protein make motor neurons sick? Nat Rev Neurosci 10:597–609PubMedCentralPubMedGoogle Scholar
  36. Butler M, Hayes CS, Chappell A, Murray SF, Yaksh TL, Hua XY (2005) Spinal distribution and metabolism of 2′-O-(2-methoxyethyl)-modified oligonucleotides after intrathecal administration in rats. Neuroscience 131:705–715PubMedGoogle Scholar
  37. Calandra S, Tarugi P, Bertolini S (2011) Altered mRNA splicing in lipoprotein disorders. Curr Opin Lipidol 22:93–99PubMedGoogle Scholar
  38. Calarco JA, Zhen M, Blencowe BJ (2011) Networking in a global world: Establishing functional connections between neural splicing regulators and their target transcripts. RNA 17(5): 775–791PubMedCentralPubMedGoogle Scholar
  39. Carroll JB, Warby SC, Southwell AL, Doty CN, Greenlee S, Skotte N, Hung G, Bennett CF, Freier SM, Hayden MR (2011) Potent and selective antisense oligonucleotides targeting single-nucleotide polymorphisms in the Huntington disease gene/allele-specific silencing of mutant huntingtin. Mol Ther: J Am Soc Gene Therapy 19:2178–2185Google Scholar
  40. Cartegni L, Krainer AR (2003) Correction of disease-associated exon skipping by synthetic exon-specific activators. Nat Struct Biol 10:120–125PubMedGoogle Scholar
  41. Carthew RW, Sontheimer EJ (2009) Origins and mechanisms of miRNAs and siRNAs. Cell 136:642–655PubMedCentralPubMedGoogle Scholar
  42. Castanotto D, Rossi JJ (2009) The promises and pitfalls of RNA-interference-based therapeutics. Nature 457:426–433PubMedCentralPubMedGoogle Scholar
  43. Castello A, Fischer B, Eichelbaum K, Horos R, Beckmann BM, Strein C, Davey NE, Humphreys DT, Preiss T, Steinmetz LM et al (2012) Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. Cell 149:1393–1406PubMedGoogle Scholar
  44. Castello A, Fischer B, Hentze MW, Preiss T (2013) z. Trends Genet 29:318–327PubMedGoogle Scholar
  45. Cech TR (1988) Ribozymes and their medical implications. JAMA 260:3030–3034PubMedGoogle Scholar
  46. Cerritelli SM, Crouch RJ (2009) Ribonuclease H: the enzymes in eukaryotes. FEBS J 276: 1494–1505PubMedCentralPubMedGoogle Scholar
  47. Chastain M, Tinoco I Jr (1993) RNA structure as related to antisense drugs. In: Lebleu STCAB (ed) Antisense research and applications. CRC, Boca Raton, FL, pp 55–66Google Scholar
  48. Chirboga C, Swoboda K, Darras B, Iannaccone S, Montes J, Allen H, Parad R, Johnson S, De Vivo D, Norris D et al (2013) Results of an open-label, escalating dose study to assess the safety, tolerability, and dose range finding of a single intrathecal dose of ISIS-SMNRx in patients with spinal muscular atrophy. In 65th American Academy of Neurology Annual Meeting, abstract S36002Google Scholar
  49. Cho S, Dreyfuss G (2010) A degron created by SMN2 exon 7 skipping is a principal contributor to spinal muscular atrophy severity. Genes Dev 24:438–442PubMedCentralPubMedGoogle Scholar
  50. Choi WY, Giraldez AJ, Schier AF (2007) Target protectors reveal dampening and balancing of Nodal agonist and antagonist by miR-430. Science 318:271–274PubMedGoogle Scholar
  51. Chu Y, Yue X, Younger ST, Janowski BA, Corey DR (2010) Involvement of argonaute proteins in gene silencing and activation by RNAs complementary to a non-coding transcript at the progesterone receptor promoter. Nucleic Acids Res 38:7736–7748PubMedCentralPubMedGoogle Scholar
  52. Cifuentes-Diaz C, Frugier T, Tiziano FD, Lacene E, Roblot N, Joshi V, Moreau MH, Melki J (2001) Deletion of murine SMN exon 7 directed to skeletal muscle leads to severe muscular dystrophy. J Cell Biol 152:1107–1114PubMedCentralPubMedGoogle Scholar
  53. Cirak S, Arechavala-Gomeza V, Guglieri M, Feng L, Torelli S, Anthony K, Abbs S, Garralda ME, Bourke J, Wells DJ et al (2011) 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 378:595–605PubMedCentralPubMedGoogle Scholar
  54. Coady TH, Lorson CL (2010) Trans-splicing-mediated improvement in a severe mouse model of spinal muscular atrophy. J Neurosci 30:126–130PubMedCentralPubMedGoogle Scholar
  55. Cooper TA, Wan L, Dreyfuss G (2009) RNA and disease. Cell 136:777–793PubMedCentralPubMedGoogle Scholar
  56. Coovert DD, Le TT, McAndrew PE, Strasswimmer J, Crawford TO, Mendell JR, Coulson SE, Androphy EJ, Prior TW, Burghes AH (1997) The survival motor neuron protein in spinal muscular atrophy. Hum Mol Genet 6:1205–1214PubMedGoogle Scholar
  57. Crawford TO, Pardo CA (1996) The neurobiology of childhood spinal muscular atrophy. Neurobiol Dis 3:97–110PubMedGoogle Scholar
  58. Crooke ST, Graham MJ, Zuckerman JE, Brooks D, Conklin BS, Cummins LL, Greig MJ, Guinosso CJ, Kornbrust D, Manoharan M et al (1996) Pharmacokinetic properties of several novel oligonucleotide analogs in mice. J Pharmacol Exp Ther 277:923–937PubMedGoogle Scholar
  59. Crooke ST, Vickers T, Lima W, Wu H (2007) Mechanisms of antisense drug action, an introduction. In: Crooke ST (ed) Antisense drug technology: principles, strategies, and applications. CRC, Boca Raton, FL, pp 3–46Google Scholar
  60. Danckwardt S, Hentze MW, Kulozik AE (2008) 3′ end mRNA processing: molecular mechanisms and implications for health and disease. EMBO J 27:482–498PubMedCentralPubMedGoogle Scholar
  61. Davis BM, McCurrach ME, Taneja KL, Singer RH, Housman DE (1997) Expansion of a CUG trinucleotide repeat in the 3′ untranslated region of myotonic dystrophy protein kinase transcripts results in nuclear retention of transcripts. Proc Natl Acad Sci U S A 94:7388–7393PubMedCentralPubMedGoogle Scholar
  62. Davis S, Propp S, Freier SM, Jones LE, Serra MJ, Kinberger G, Bhat B, Swayze EE, Bennett CF, Esau C (2009) Potent inhibition of microRNA in vivo without degradation. Nucleic Acids Res 37:70–77PubMedCentralPubMedGoogle Scholar
  63. De Sandre-Giovannoli A, Bernard R, Cau P, Navarro C, Amiel J, Boccaccio I, Lyonnet S, Stewart CL, Munnich A, Le Merrer M et al (2003) Lamin a truncation in Hutchinson-Gilford progeria. Science 300:2055PubMedGoogle Scholar
  64. Dechat T, Pfleghaar K, Sengupta K, Shimi T, Shumaker DK, Solimando L, Goldman RD (2008) Nuclear lamins: major factors in the structural organization and function of the nucleus and chromatin. Genes Dev 22:832–853PubMedCentralPubMedGoogle Scholar
  65. DeJesus-Hernandez M, Mackenzie IR, Boeve BF, Boxer AL, Baker M, Rutherford NJ, Nicholson AM, Finch NA, Flynn H, Adamson J et al (2011) Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 72:245–256PubMedCentralPubMedGoogle Scholar
  66. Devos SL, Miller TM (2013) Direct intraventricular delivery of drugs to the rodent central nervous system. J Vis Exp 75:e50326PubMedGoogle Scholar
  67. Dickson A, Osman E, Lorson CL (2008) A negatively acting bifunctional RNA increases survival motor neuron both in vitro and in vivo. Hum Gene Ther 19:1307–1315PubMedCentralPubMedGoogle Scholar
  68. Djebali S, Davis CA, Merkel A, Dobin A, Lassmann T, Mortazavi A, Tanzer A, Lagarde J, Lin W, Schlesinger F et al (2012) Landscape of transcription in human cells. Nature 489:101–108PubMedCentralPubMedGoogle Scholar
  69. Doench JG, Petersen CP, Sharp PA (2003) siRNAs can function as miRNAs. Genes Dev 17:438–442PubMedCentralPubMedGoogle Scholar
  70. Dominguez E, Marais T, Chatauret N, Benkhelifa-Ziyyat S, Duque S, Ravassard P, Carcenac R, Astord S, de Moura AP, Voit T et al (2011) Intravenous scAAV9 delivery of a codon-optimized SMN1 sequence rescues SMA mice. Hum Mol Genet 20:681–693PubMedGoogle Scholar
  71. Dominski Z, Kole R (1993) Restoration of correct splicing in thalassemic pre-mRNA by antisense oligonucleotides. Proc Natl Acad Sci U S A 90:8673–8677PubMedCentralPubMedGoogle Scholar
  72. Du H, Cline MS, Osborne RJ, Tuttle DL, Clark TA, Donohue JP, Hall MP, Shiue L, Swanson MS, Thornton CA et al (2010) Aberrant alternative splicing and extracellular matrix gene expression in mouse models of myotonic dystrophy. Nat Struct Mol Biol 17:187–193PubMedCentralPubMedGoogle Scholar
  73. Dunckley MG, Manoharan M, Villiet P, Eperon IC, Dickson G (1998) Modification of splicing in the dystrophin gene in cultured Mdx muscle cells by antisense oligoribonucleotides. Hum Mol Genet 7:1083–1090PubMedGoogle Scholar
  74. Echeverria GV, Cooper TA (2012) RNA-binding proteins in microsatellite expansion disorders: mediators of RNA toxicity. Brain Res 1462:100–111PubMedCentralPubMedGoogle Scholar
  75. Ecker DJ (1993) Strategies for invasion of RNA secondary structure. In: Lebleu STCAB (ed) Antisense research and applications. CRC, Boca Raton, FL, pp 387–400Google Scholar
  76. Eckstein F (2000) Phosphorothioate oligodeoxynucleotides: what is their origin and what is unique about them? Antisense Nucleic Acid Drug Dev 10:117–121PubMedGoogle Scholar
  77. Egli M, Pallan PS, Allerson CR, Prakash TP, Berdeja A, Yu J, Lee S, Watt A, Gaus H, Bhat B et al (2011) Synthesis, improved antisense activity and structural rationale for the divergent RNA affinities of 3′-fluoro hexitol nucleic acid (FHNA and Ara-FHNA) modified oligonucleotides. J Am Chem Soc 133:16642–16649PubMedCentralPubMedGoogle Scholar
  78. El-Matary W, Kotagiri S, Cameron D, Peart I (2004) Spinal muscle atrophy type 1 (Werdnig-Hoffman disease) with complex cardiac malformation. Eur J Pediatr 163:331–332PubMedGoogle Scholar
  79. Elbashir SM, Harborth J, Lendeckel W, Yalcin A, Weber K, Tuschl T (2001) Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature 411:494–498PubMedGoogle Scholar
  80. Elmen J, Lindow M, Schutz S, Lawrence M, Petri A, Obad S, Lindholm M, Hedtjarn M, Hansen HF, Berger U et al (2008) LNA-mediated microRNA silencing in non-human primates. Nature 452:896–899PubMedGoogle Scholar
  81. Eriksson M, Brown WT, Gordon LB, Glynn MW, Singer J, Scott L, Erdos MR, Robbins CM, Moses TY, Berglund P et al (2003) Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. Nature 423:293–298PubMedGoogle Scholar
  82. Esau C, Davis S, Murray SF, Yu XX, Pandey SK, Pear M, Watts L, Booten SL, Graham M, McKay R et al (2006) miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting. Cell Metab 3:87–98PubMedGoogle Scholar
  83. Esau C, Kang X, Peralta E, Hanson E, Marcusson EG, Ravichandran LV, Sun Y, Koo S, Perera RJ, Jain R et al (2004) MicroRNA-143 regulates adipocyte differentiation. J Biol Chem 279:52361–52365PubMedGoogle Scholar
  84. Faghihi MA, Kocerha J, Modarresi F, Engstrom PG, Chalk AM, Brothers SP, Koesema E, St Laurent G, Wahlestedt C (2010) RNAi screen indicates widespread biological function for human natural antisense transcripts. PLoS One 5Google Scholar
  85. Faghihi MA, Wahlestedt C (2009) Regulatory roles of natural antisense transcripts. Nat Rev Mol Cell Biol 10:637–643PubMedCentralPubMedGoogle Scholar
  86. Fallini C, Bassell GJ, Rossoll W (2012) Spinal muscular atrophy: the role of SMN in axonal mRNA regulation. Brain Res 1462:81–92PubMedCentralPubMedGoogle Scholar
  87. Fardaei M, Larkin K, Brook JD, Hamshere MG (2001) In vivo co-localisation of MBNL protein with DMPK expanded-repeat transcripts. Nucleic Acids Res 29:2766–2771PubMedCentralPubMedGoogle Scholar
  88. Feldkotter M, Schwarzer V, Wirth R, Wienker TF, Wirth B (2002) Quantitative analyses of SMN1 and SMN2 based on real-time light Cycler PCR: fast and highly reliable carrier testing and prediction of severity of spinal muscular atrophy. Am J Hum Genet 70:358–368PubMedCentralPubMedGoogle Scholar
  89. Fiszer A, Mykowska A, Krzyzosiak WJ (2011) Inhibition of mutant huntingtin expression by RNA duplex targeting expanded CAG repeats. Nucleic Acids Res 39:5578–5585PubMedCentralPubMedGoogle Scholar
  90. Fong LG, Ng JK, Lammerding J, Vickers TA, Meta M, Cote N, Gavino B, Qiao X, Chang SY, Young SR et al (2006) Prelamin A and lamin A appear to be dispensable in the nuclear lamina. J Clin Invest 116:743–752PubMedCentralPubMedGoogle Scholar
  91. Foust KD, Wang X, McGovern VL, Braun L, Bevan AK, Haidet AM, Le TT, Morales PR, Rich MM, Burghes AH et al (2010) Rescue of the spinal muscular atrophy phenotype in a mouse model by early postnatal delivery of SMN. Nat Biotechnol 28:271–274PubMedCentralPubMedGoogle Scholar
  92. Francois V, Klein AF, Beley C, Jollet A, Lemercier C, Garcia L, Furling D (2011) Selective silencing of mutated mRNAs in DM1 by using modified hU7-snRNAs. Nat Struct Mol Biol 18:85–87PubMedGoogle Scholar
  93. Freier SM, Lima WF, Sanghvi YS, Vickers T, Zounes M, Cook PD, Ecker DJ (1992) Thermodynamics of antisense oligonucleotide hybridization. In: Izant RPEAJG (ed) Gene regulation: biology of antisense RNA and DNA. Raven, New York, NY, pp 95–107Google Scholar
  94. Fukuyama Y, Osawa M, Suzuki H (1981) Congenital progressive muscular dystrophy of the Fukuyama type—clinical, genetic and pathological considerations. Brain Dev 3:1–29PubMedGoogle Scholar
  95. Gabanella F, Butchbach ME, Saieva L, Carissimi C, Burghes AH, Pellizzoni L (2007) Ribonucleoprotein assembly defects correlate with spinal muscular atrophy severity and preferentially affect a subset of spliceosomal snRNPs. PLoS One 2:e921PubMedCentralPubMedGoogle Scholar
  96. Gagnon KT, Corey DR (2012) Argonaute and the nuclear RNAs: new pathways for RNA-mediated control of gene expression. Nucleic Acid Ther 22:3–16PubMedCentralPubMedGoogle Scholar
  97. Gagnon KT, Pendergraff HM, Deleavey GF, Swayze EE, Potier P, Randolph J, Roesch EB, Chattopadhyaya J, Damha MJ, Bennett CF et al (2010) Allele-selective inhibition of mutant huntingtin expression with antisense oligonucleotides targeting the expanded CAG repeat. Biochemistry 49:10166–10178PubMedCentralPubMedGoogle Scholar
  98. Gao Z, Cooper TA (2013) Antisense oligonucleotides: rising stars in eliminating RNA toxicity in myotonic dystrophy. Hum Gene Ther 24:499–507PubMedCentralPubMedGoogle Scholar
  99. Gatchel JR, Zoghbi HY (2005) Diseases of unstable repeat expansion: mechanisms and common principles. Nat Rev Genet 6:743–755PubMedGoogle Scholar
  100. Geary RS (2009) Antisense oligonucleotide pharmacokinetics and metabolism. Expert Opin Drug Metab Toxicol 5:381–391PubMedGoogle Scholar
  101. Geary RS, Wancewicz E, Matson J, Pearce M, Siwkowski A, Swayze E, Bennett F (2009) Effect of dose and plasma concentration on liver uptake and pharmacologic activity of a 2′-methoxyethyl modified chimeric antisense oligonucleotide targeting PTEN. Biochem Pharmacol 78:284–291PubMedGoogle Scholar
  102. Geary RS, Yu RZ, Siwkowski A, Levin AA (2007) Pharmacokinetic/pharmacodynamic properties of phosphorothioate 2′-O-(2-methoxyethyl)-modified antisense oligonucleotides in animals and man. In: Crooke ST (ed) Antisense drug technology: principles, strategies, and applications. CRC, Boca Raton, FL, pp 305–326Google Scholar
  103. Geib T, Hertel KJ (2009) Restoration of full-length SMN promoted by adenoviral vectors expressing RNA antisense oligonucleotides embedded in U7 snRNAs. PLoS One 4:e8204PubMedCentralPubMedGoogle Scholar
  104. Ghildiyal M, Zamore PD (2009) Small silencing RNAs: an expanding universe. Nat Rev Genet 10:94–108PubMedCentralPubMedGoogle Scholar
  105. Gilleron J, Querbes W, Zeigerer A, Borodovsky A, Marsico G, Schubert U, Manygoats K, Seifert S, Andree C, Stoter M et al (2013) Image-based analysis of lipid nanoparticle-mediated siRNA delivery, intracellular trafficking and endosomal escape. Nat Biotechnol 31:638–646PubMedGoogle Scholar
  106. Goemans NM, Tulinius M, van den Akker JT, Burm BE, Ekhart PF, Heuvelmans N, Holling T, Janson AA, Platenburg GJ, Sipkens JA et al (2011) Systemic administration of PRO051 in Duchenne’s muscular dystrophy. N Engl J Med 364:1513–1522PubMedGoogle Scholar
  107. Gogliotti RG, Hammond SM, Lutz C, Didonato CJ (2010) Molecular and phenotypic reassessment of an infrequently used mouse model for spinal muscular atrophy. Biochem Biophys Res Commun 391:517–522PubMedCentralPubMedGoogle Scholar
  108. Goraczniak R, Behlke MA, Gunderson SI (2009) Gene silencing by synthetic U1 adaptors. Nat Biotechnol 27:257–263PubMedGoogle Scholar
  109. Guan L, Disney MD (2012) Recent advances in developing small molecules targeting RNA. ACS Chem Biol 7:73–86PubMedGoogle Scholar
  110. Gunderson SI, Polycarpou-Schwarz M, Mattaj IW (1998) U1 snRNP inhibits pre-mRNA polyadenylation through a direct interaction between U1 70K and poly(A) polymerase. Mol Cell 1:255–264PubMedGoogle Scholar
  111. Gutschner T, Hammerle M, Eissmann M, Hsu J, Kim Y, Hung G, Revenko A, Arun G, Stentrup M, Gross M et al (2013) The noncoding RNA MALAT1 is a critical regulator of the metastasis phenotype of lung cancer cells. Cancer Res 73:1180–1189PubMedCentralPubMedGoogle Scholar
  112. Guttman M, Rinn JL (2012) Modular regulatory principles of large non-coding RNAs. Nature 482:339–346PubMedGoogle Scholar
  113. Guttman M, Russell P, Ingolia NT, Weissman JS, Lander ES (2013) Ribosome profiling provides evidence that large noncoding RNAs do not encode proteins. Cell 154:240–251PubMedCentralPubMedGoogle Scholar
  114. Hall JW 3rd (2000) Development of the ear and hearing. J Perinatol 20:S12–S20PubMedGoogle Scholar
  115. Hamilton G, Gillingwater TH (2013) Spinal muscular atrophy: going beyond the motor neuron. Trends Mol Med 19:40–50PubMedGoogle Scholar
  116. Han J, Kim D, Morris KV (2007) Promoter-associated RNA is required for RNA-directed transcriptional gene silencing in human cells. Proc Natl Acad Sci U S A 104:12422–12427PubMedCentralPubMedGoogle Scholar
  117. Hanecak R, Brown-Driver V, Fox MC, Azad RF, Furusako S, Nozaki C, Ford C, Sasmor H, Anderson KP (1996) Antisense oligonucleotide inhibition of hepatitis C virus gene expression in transformed hepatocytes. J Virol 70:5203–5212PubMedCentralPubMedGoogle Scholar
  118. Harper PS, Brook JD, Newman E (2001) Myotonic dystrophy. WB Saunders, London, UKGoogle Scholar
  119. Havens MA, Duelli DM, Hastings ML (2013) Targeting RNA splicing for disease therapy. Wiley Interdiscip Rev RNA 4:247–266PubMedCentralPubMedGoogle Scholar
  120. He Y, Vogelstein B, Velculescu VE, Papadopoulos N, Kinzler KW (2008) The antisense transcriptomes of human cells. Science 322:1855–1857PubMedCentralPubMedGoogle Scholar
  121. Heier CR, Satta R, Lutz C, DiDonato CJ (2010) Arrhythmia and cardiac defects are a feature of spinal muscular atrophy model mice. Hum Mol Genet 19:3906–3918PubMedCentralPubMedGoogle Scholar
  122. Helene C, Toulme JJ (1990) Specific regulation of gene expression by antisense, sense and antigene nucleic acids. Biochim Biophys Acta 1049:99–125PubMedGoogle Scholar
  123. Henry SP, Giclas PC, Leeds J, Pangburn M, Auletta C, Levin AA, Kornbrust DJ (1997) Activation of the alternative pathway of complement by a phosphorothioate oligonucleotide: potential mechanism of action. J Pharmacol Exp Ther 281:810–816PubMedGoogle Scholar
  124. Henry SP, Kim T-W, Kramer-Strickland K, Zanardi TA, Fey RA, Levin AA (2007) Toxicologic properties of 2′O-methoxyethyl chimeric antisense inhibitors in animals and man. In: Crooke ST (ed) Antisense drug technology: principles, strategies and applications. CRC, Boca Raton, FL, pp 327–364Google Scholar
  125. Hong DS, Younes A, Fayad L, Fowler NH, Hagemeister FB, Mistry R, Nemunaitis JJ, Borad MJ, Bryce AH, Yamashita M, et al (2013) A phase I study of ISIS 481464 (AZD9150), a first-in-human, first-in-class, antisense oligonucleotide inhibitor of STAT3, in patients with advanced cancers. In American Society of Clinical Oncology Annual Meeting, abstract 8523Google Scholar
  126. Hsieh-Li HM, Chang JG, Jong YJ, Wu MH, Wang NM, Tsai CH, Li H (2000) A mouse model for spinal muscular atrophy. Nat Genet 24:66–70PubMedGoogle Scholar
  127. Hu J, Liu J, Corey DR (2010) Allele-selective inhibition of huntingtin expression by switching to an miRNA-like RNAi mechanism. Chem Biol 17:1183–1188PubMedCentralPubMedGoogle Scholar
  128. Hu J, Matsui M, Gagnon KT, Schwartz JC, Gabillet S, Arar K, Wu J, Bezprozvanny I, Corey DR (2009) Allele-specific silencing of mutant huntingtin and ataxin-3 genes by targeting expanded CAG repeats in mRNAs. Nat Biotechnol 27:478–484PubMedCentralPubMedGoogle Scholar
  129. Hua Y, Sahashi K, Hung G, Rigo F, Passini MA, Bennett CF, Krainer AR (2010) Antisense correction of SMN2 splicing in the CNS rescues necrosis in a type III SMA mouse model. Genes Dev 24:1634–1644PubMedCentralPubMedGoogle Scholar
  130. Hua Y, Sahashi K, Rigo F, Hung G, Horev G, Bennett CF, Krainer AR (2011) Peripheral SMN restoration is essential for long-term rescue of a severe spinal muscular atrophy mouse model. Nature 478:123–126PubMedCentralPubMedGoogle Scholar
  131. Hua Y, Vickers TA, Baker BF, Bennett CF, Krainer AR (2007) Enhancement of SMN2 exon 7 inclusion by antisense oligonucleotides targeting the exon. PLoS Biol 5:e73PubMedCentralPubMedGoogle Scholar
  132. Hua Y, Vickers TA, Okunola HL, Bennett CF, Krainer AR (2008) Antisense masking of an hnRNP A1/A2 intronic splicing silencer corrects SMN2 splicing in transgenic mice. Am J Hum Genet 82:834–848PubMedCentralPubMedGoogle Scholar
  133. Huntzinger E, Izaurralde E (2011) Gene silencing by microRNAs: contributions of translational repression and mRNA decay. Nat Rev Genet 12:99–110PubMedGoogle Scholar
  134. Hutvagner G, Zamore PD (2002) A microRNA in a multiple-turnover RNAi enzyme complex. Science 297:2056–2060PubMedGoogle Scholar
  135. Ivanova G, Reigadas S, Ittig D, Arzumanov A, Andreola ML, Leumann C, Toulme JJ, Gait MJ (2007) Tricyclo-DNA containing oligonucleotides as steric block inhibitors of human immunodeficiency virus type 1 tat-dependent trans-activation and HIV-1 infectivity. Oligonucleotides 17:54–65PubMedGoogle Scholar
  136. Iversen PL (2007) Morpholinos. In: Crooke ST (ed) Antisense drug technology: principles, strategies, and applications. CRC, Boca Raton, FL, pp 565–582Google Scholar
  137. Jackson AL, Burchard J, Leake D, Reynolds A, Schelter J, Guo J, Johnson JM, Lim L, Karpilow J, Nichols K et al (2006) Position-specific chemical modification of siRNAs reduces “off-target” transcript silencing. RNA 12:1197–1205PubMedCentralPubMedGoogle Scholar
  138. Jackson AL, Linsley PS (2010) Recognizing and avoiding siRNA off-target effects for target identification and therapeutic application. Nat Rev Drug Discov 9:57–67PubMedGoogle Scholar
  139. Janowski BA, Huffman KE, Schwartz JC, Ram R, Hardy D, Shames DS, Minna JD, Corey DR (2005) Inhibiting gene expression at transcription start sites in chromosomal DNA with antigene RNAs. Nat Chem Biol 1:216–222PubMedGoogle Scholar
  140. Janowski BA, Younger ST, Hardy DB, Ram R, Huffman KE, Corey DR (2007) Activating gene expression in mammalian cells with promoter-targeted duplex RNAs. Nat Chem Biol 3:166–173PubMedGoogle Scholar
  141. Janssen HL, Reesink HW, Lawitz EJ, Zeuzem S, Rodriguez-Torres M, Patel K, van der Meer AJ, Patick AK, Chen A, Zhou Y et al (2013) Treatment of HCV infection by targeting microRNA. N Engl J Med 368:1685–1694PubMedGoogle Scholar
  142. Jayaraman M, Ansell SM, Mui BL, Tam YK, Chen J, Du X, Butler D, Eltepu L, Matsuda S, Narayanannair JK et al (2012) Maximizing the potency of siRNA lipid nanoparticles for hepatic gene silencing in vivo. Angewandte Chemie 51:8529–8533PubMedCentralPubMedGoogle Scholar
  143. Jiang H, Mankodi A, Swanson MS, Moxley RT, Thornton CA (2004) 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 13:3079–3088PubMedGoogle Scholar
  144. Jurica MS, Moore MJ (2003) Pre-mRNA splicing: awash in a sea of proteins. Mol Cell 12:5–14PubMedGoogle Scholar
  145. Kaida D, Berg MG, Younis I, Kasim M, Singh LN, Wan L, Dreyfuss G (2010) U1 snRNP protects pre-mRNAs from premature cleavage and polyadenylation. Nature 468:664–668PubMedCentralPubMedGoogle Scholar
  146. Kalsotra A, Cooper TA (2011) Functional consequences of developmentally regulated alternative splicing. Nat Rev Genet 12:715–729PubMedCentralPubMedGoogle Scholar
  147. Kanadia RN, Shin J, Yuan Y, Beattie SG, Wheeler TM, Thornton CA, Swanson MS (2006) Reversal of RNA missplicing and myotonia after muscleblind overexpression in a mouse poly(CUG) model for myotonic dystrophy. Proc Natl Acad Sci U S A 103:11748–11753PubMedCentralPubMedGoogle Scholar
  148. Kapeli K, Yeo GW (2012) Genome-wide approaches to dissect the roles of RNA binding proteins in translational control: implications for neurological diseases. Front Neurosci 6:144PubMedCentralPubMedGoogle Scholar
  149. Katayama S, Tomaru Y, Kasukawa T, Waki K, Nakanishi M, Nakamura M, Nishida H, Yap CC, Suzuki M, Kawai J et al (2005) Antisense transcription in the mammalian transcriptome. Science 309:1564–1566PubMedGoogle Scholar
  150. Kim DH, Saetrom P, Snove O Jr, Rossi JJ (2008) MicroRNA-directed transcriptional gene silencing in mammalian cells. Proc Natl Acad Sci U S A 105:16230–16235PubMedCentralPubMedGoogle Scholar
  151. Kim DH, Villeneuve LM, Morris KV, Rossi JJ (2006) Argonaute-1 directs siRNA-mediated transcriptional gene silencing in human cells. Nat Struct Mol Biol 13:793–797PubMedGoogle Scholar
  152. Kim HJ, Kim NC, Wang YD, Scarborough EA, Moore J, Diaz Z, MacLea KS, Freibaum B, Li S, Molliex A et al (2013) Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS. Nature 495:467–473PubMedCentralPubMedGoogle Scholar
  153. Kinali M, Arechavala-Gomeza V, Feng L, Cirak S, Hunt D, Adkin C, Guglieri M, Ashton E, Abbs S, Nihoyannopoulos P et al (2009) 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 8:918–928PubMedCentralPubMedGoogle Scholar
  154. Kislauskis EH, Zhu X, Singer RH (1994) Sequences responsible for intracellular localization of beta-actin messenger RNA also affect cell phenotype. J Cell Biol 127:441–451PubMedGoogle Scholar
  155. Kleinman ME, Yamada K, Takeda A, Chandrasekaran V, Nozaki M, Baffi JZ, Albuquerque RJ, Yamasaki S, Itaya M, Pan Y et al (2008) Sequence- and target-independent angiogenesis suppression by siRNA via TLR3. Nature 452:591–597PubMedCentralPubMedGoogle Scholar
  156. Kole R, Krainer AR, Altman S (2012) RNA therapeutics: beyond RNA interference and antisense oligonucleotides. Nat Rev Drug Discov 11:125–140PubMedGoogle Scholar
  157. Koller E, Vincent TM, Chappell A, De S, Manoharan M, Bennett CF (2011) Mechanisms of single-stranded phosphorothioate modified antisense oligonucleotide accumulation in hepatocytes. Nucleic Acids Res 39:4795–4807PubMedCentralPubMedGoogle Scholar
  158. Koo T, Wood MJ (2013) Clinical trials using antisense oligonucleotides in Duchenne muscular dystrophy. Hum Gene Ther 24:479–488PubMedGoogle Scholar
  159. Kordasiewicz HB, Stanek LM, Wancewicz EV, Mazur C, McAlonis MM, Pytel KA, Artates JW, Weiss A, Cheng SH, Shihabuddin LS et al (2012) Sustained therapeutic reversal of Huntington’s disease by transient repression of huntingtin synthesis. Neuron 74:1031–1044PubMedCentralPubMedGoogle Scholar
  160. Kornblihtt AR, de la Mata M, Fededa JP, Munoz MJ, Nogues G (2004) Multiple links between transcription and splicing. RNA 10:1489–1498PubMedCentralPubMedGoogle Scholar
  161. Koval ED, Shaner C, Zhang P, du Maine X, Fischer K, Tay J, Chau BN, Wu GF, Miller TM (2013) Method for widespread microRNA-155 inhibition prolongs survival in ALS-model mice. Hum Mol Genet 22(20):4127–4135PubMedGoogle Scholar
  162. Krawczak M, Reiss J, Cooper DN (1992) The mutational spectrum of single base-pair substitutions in mRNA splice junctions of human genes: causes and consequences. Hum Genet 90:41–54PubMedGoogle Scholar
  163. Kremer H, van Wijk E, Marker T, Wolfrum U, Roepman R (2006) Usher syndrome: molecular links of pathogenesis, proteins and pathways. Hum Mol Genet 15(Spec No 2):R262–R270PubMedGoogle Scholar
  164. Krieg AM (2008) Toll-like receptor 9 (TLR9) agonists in the treatment of cancer. Oncogene 27:161–167PubMedGoogle Scholar
  165. Krol J, Fiszer A, Mykowska A, Sobczak K, de Mezer M, Krzyzosiak WJ (2007) Ribonuclease dicer cleaves triplet repeat hairpins into shorter repeats that silence specific targets. Mol Cell 25:575–586PubMedGoogle Scholar
  166. Krutzfeldt J, Rajewsky N, Braich R, Rajeev KG, Tuschl T, Manoharan M, Stoffel M (2005) Silencing of microRNAs in vivo with ‘antagomirs’. Nature 438:685–689PubMedGoogle Scholar
  167. Kuyumcu-Martinez NM, Wang GS, Cooper TA (2007) Increased steady-state levels of CUGBP1 in myotonic dystrophy 1 are due to PKC-mediated hyperphosphorylation. Mol Cell 28:68–78PubMedCentralPubMedGoogle Scholar
  168. Kwoh TJ (2007) An overview of the clinical safety experience of first- and second-generation antisense oligonucleotides. In: Crooke ST (ed) Antisense drug technology: principles, strategies, and applications. CRC, Boca Raton, FL, pp 365–399Google Scholar
  169. Lam MT, Cho H, Lesch HP, Gosselin D, Heinz S, Tanaka-Oishi Y, Benner C, Kaikkonen MU, Kim AS, Kosaka M et al (2013) Rev-Erbs repress macrophage gene expression by inhibiting enhancer-directed transcription. Nature 498:511–515PubMedGoogle Scholar
  170. Langlois MA, Boniface C, Wang G, Alluin J, Salvaterra PM, Puymirat J, Rossi JJ, Lee NS (2005) Cytoplasmic and nuclear retained DMPK mRNAs are targets for RNA interference in myotonic dystrophy cells. J Biol Chem 280:16949–16954PubMedGoogle Scholar
  171. Le TT, Pham LT, Butchbach ME, Zhang HL, Monani UR, Coovert DD, Gavrilina TO, Xing L, Bassell GJ, Burghes AH (2005) SMNDelta7, the major product of the centromeric survival motor neuron (SMN2) gene, extends survival in mice with spinal muscular atrophy and associates with full-length SMN. Hum Mol Genet 14:845–857PubMedGoogle Scholar
  172. Lee JE, Bennett CF, Cooper TA (2012) RNase H-mediated degradation of toxic RNA in myotonic dystrophy type 1. Proc Natl Acad Sci U S A 109:4221–4226PubMedCentralPubMedGoogle Scholar
  173. Lee JT (2012) Epigenetic regulation by long noncoding RNAs. Science 338:1435–1439PubMedGoogle Scholar
  174. Lee RG, Crosby J, Baker BF, Graham MJ, Crooke RM (2013) Antisense technology: an emerging platform for cardiovascular disease therapeutics. J Cardiovasc Transl Res 6(6):969–980PubMedCentralPubMedGoogle Scholar
  175. Lefave CV, Squatrito M, Vorlova S, Rocco GL, Brennan CW, Holland EC, Pan YX, Cartegni L (2011) Splicing factor hnRNPH drives an oncogenic splicing switch in gliomas. EMBO J 30(19):4084–4097PubMedCentralPubMedGoogle Scholar
  176. Lefebvre S, Burglen L, Reboullet S, Clermont O, Burlet P, Viollet L, Benichou B, Cruaud C, Millasseau P, Zeviani M et al (1995) Identification and characterization of a spinal muscular atrophy-determining gene. Cell 80:155–165PubMedGoogle Scholar
  177. Lefebvre S, Burlet P, Liu Q, Bertrandy S, Clermont O, Munnich A, Dreyfuss G, Melki J (1997) Correlation between severity and SMN protein level in spinal muscular atrophy. Nat Genet 16:265–269PubMedGoogle Scholar
  178. Leger AJ, Mosquea LM, Clayton NP, Wu IH, Weeden T, Nelson CA, Phillips L, Roberts E, Piepenhagen PA, Cheng SH et al (2013) Systemic delivery of a peptide-linked morpholino oligonucleotide neutralizes mutant RNA toxicity in a mouse model of myotonic dystrophy. Nucleic Acid Ther 23:109–117PubMedGoogle Scholar
  179. Lentz J, Pan F, Ng SS, Deininger P, Keats B (2007) Ush1c216A knock-in mouse survives Katrina. Mutat Res 616:139–144PubMedGoogle Scholar
  180. Lentz J, Savas S, Ng SS, Athas G, Deininger P, Keats B (2005) The USH1C 216G– > A splice-site mutation results in a 35-base-pair deletion. Hum Genet 116:225–227PubMedGoogle Scholar
  181. Lentz JJ, Gordon WC, Farris HE, MacDonald GH, Cunningham DE, Robbins CA, Tempel BL, Bazan NG, Rubel EW, Oesterle EC et al (2010) Deafness and retinal degeneration in a novel USH1C knock-in mouse model. Dev Neurobiol 70:253–267PubMedCentralPubMedGoogle Scholar
  182. Lentz JJ, Jodelka FM, Hinrich AJ, McCaffrey KE, Farris HE, Spalitta MJ, Bazan NG, Duelli DM, Rigo F, Hastings ML (2013) Rescue of hearing and vestibular function by antisense oligonucleotides in a mouse model of human deafness. Nat Med 19:345–350PubMedCentralPubMedGoogle Scholar
  183. Levin AA, Yu RZ, Geary RS (2007) Basic principles of the pharmacokinetics of antisense oligonucleotide drugs. In: Crooke ST (ed) Antisense drug technology: principles, strategies, and applications. CRC, Boca Raton, FL, pp 183–215Google Scholar
  184. Li LC, Okino ST, Zhao H, Pookot D, Place RF, Urakami S, Enokida H, Dahiya R (2006) Small dsRNAs induce transcriptional activation in human cells. Proc Natl Acad Sci U S A 103:17337–17342PubMedCentralPubMedGoogle Scholar
  185. Liang XH, Vickers TA, Guo S, Crooke ST (2011) Efficient and specific knockdown of small non-coding RNAs in mammalian cells and in mice. Nucleic Acids Res 39:e13PubMedCentralPubMedGoogle Scholar
  186. Licatalosi DD, Darnell RB (2010) RNA processing and its regulation: global insights into biological networks. Nat Rev Genet 11:75–87PubMedCentralPubMedGoogle Scholar
  187. Lightfoot HL, Hall J (2012) Target mRNA inhibition by oligonucleotide drugs in man. Nucleic Acids Res 40:10585–10595PubMedCentralPubMedGoogle Scholar
  188. Lim KH, Ferraris L, Filloux ME, Raphael BJ, Fairbrother WG (2011) Using positional distribution to identify splicing elements and predict pre-mRNA processing defects in human genes. Proc Natl Acad Sci U S A 108:11093–11098PubMedCentralPubMedGoogle Scholar
  189. Lim SR, Hertel KJ (2001) Modulation of survival motor neuron pre-mRNA splicing by inhibition of alternative 3′ splice site pairing. J Biol Chem 276:45476–45483PubMedGoogle Scholar
  190. Lima W, Wu H, Crooke ST (2007) The RNase H mechanism. In: Crooke ST (ed) Antisense drug technology: principles, strategies, and applications. CRC, Boca Raton, FL, pp 47–74Google Scholar
  191. Lima WF, Monia BP, Ecker DJ, Freier SM (1992) Implication of RNA structure on antisense oligonucleotide hybridization kinetics. Biochemistry 31:12055–12061PubMedGoogle Scholar
  192. Lima WF, Prakash TP, Murray HM, Kinberger GA, Li W, Chappell AE, Li CS, Murray SF, Gaus H, Seth PP et al (2012) Single-stranded siRNAs activate RNAi in animals. Cell 150:883–894PubMedGoogle Scholar
  193. Lin F, Worman HJ (1993) Structural organization of the human gene encoding nuclear lamin A and nuclear lamin C. J Biol Chem 268:16321–16326PubMedGoogle Scholar
  194. Lin X, Miller JW, Mankodi A, Kanadia RN, Yuan Y, Moxley RT, Swanson MS, Thornton CA (2006) Failure of MBNL1-dependent post-natal splicing transitions in myotonic dystrophy. Hum Mol Genet 15:2087–2097PubMedGoogle Scholar
  195. Liu J, Hu J, Corey DR (2011) Expanding the action of duplex RNAs into the nucleus: redirecting alternative splicing. Nucleic Acids Res 40(3):1240–1250PubMedCentralPubMedGoogle Scholar
  196. Lorenz P, Misteli T, Baker BF, Bennett CF, Spector DL (2000) Nucleocytoplasmic shuttling: a novel in vivo property of antisense phosphorothioate oligodeoxynucleotides. Nucleic Acids Res 28:582–592PubMedCentralPubMedGoogle Scholar
  197. Lorson CL, Androphy EJ (2000) An exonic enhancer is required for inclusion of an essential exon in the SMA-determining gene SMN. Hum Mol Genet 9:259–265PubMedGoogle Scholar
  198. Lorson CL, Hahnen E, Androphy EJ, Wirth B (1999) A single nucleotide in the SMN gene regulates splicing and is responsible for spinal muscular atrophy. Proc Natl Acad Sci U S A 96:6307–6311PubMedCentralPubMedGoogle Scholar
  199. Lunn MR, Wang CH (2008) Spinal muscular atrophy. Lancet 371:2120–2133PubMedGoogle Scholar
  200. Mahadevan M, Tsilfidis C, Sabourin L, Shutler G, Amemiya C, Jansen G, Neville C, Narang M, Barcelo J, O’Hoy K et al (1992) Myotonic dystrophy mutation: an unstable CTG repeat in the 3′ untranslated region of the gene. Science 255:1253–1255PubMedGoogle Scholar
  201. Maniatis T, Reed R (2002) An extensive network of coupling among gene expression machines. Nature 416:499–506PubMedGoogle Scholar
  202. Mankodi A, Logigian E, Callahan L, McClain C, White R, Henderson D, Krym M, Thornton CA (2000) Myotonic dystrophy in transgenic mice expressing an expanded CUG repeat. Science 289:1769–1773PubMedGoogle Scholar
  203. Mankodi A, Takahashi MP, Jiang H, Beck CL, Bowers WJ, Moxley RT, Cannon SC, Thornton CA (2002) Expanded CUG repeats trigger aberrant splicing of ClC-1 chloride channel pre-mRNA and hyperexcitability of skeletal muscle in myotonic dystrophy. Mol Cell 10:35–44PubMedGoogle Scholar
  204. Mankodi A, Urbinati CR, Yuan QP, Moxley RT, Sansone V, Krym M, Henderson D, Schalling M, Swanson MS, Thornton CA (2001) Muscleblind localizes to nuclear foci of aberrant RNA in myotonic dystrophy types 1 and 2. Hum Mol Genet 10:2165–2170PubMedGoogle Scholar
  205. Mann CJ, Honeyman K, Cheng AJ, Ly T, Lloyd F, Fletcher S, Morgan JE, Partridge TA, Wilton SD (2001) Antisense-induced exon skipping and synthesis of dystrophin in the mdx mouse. Proc Natl Acad Sci U S A 98:42–47PubMedCentralPubMedGoogle Scholar
  206. Manoharan M, Akinc A, Pandey RK, Qin J, Hadwiger P, John M, Mills K, Charisse K, Maier MA, Nechev L et al (2011) Unique gene-silencing and structural properties of 2′-fluoro-modified siRNAs. Angewandte Chemie 50:2284–2288PubMedCentralPubMedGoogle Scholar
  207. Marques JT, Williams BR (2005) Activation of the mammalian immune system by siRNAs. Nat Biotechnol 23:1399–1405PubMedGoogle Scholar
  208. Martin KC, Ephrussi A (2009) mRNA localization: gene expression in the spatial dimension. Cell 136:719–730PubMedCentralPubMedGoogle Scholar
  209. Mattick JS (2009) The genetic signatures of noncoding RNAs. PLoS Genet 5:e1000459PubMedCentralPubMedGoogle Scholar
  210. Matveeva O, Nechipurenko Y, Rossi L, Moore B, Saetrom P, Ogurtsov AY, Atkins JF, Shabalina SA (2007) Comparison of approaches for rational siRNA design leading to a new efficient and transparent method. Nucleic Acids Res 35:e63PubMedCentralPubMedGoogle Scholar
  211. Matveeva OV, Shabalina SA, Nemtsov VA, Tsodikov AD, Gesteland RF, Atkins JF (2003) Thermodynamic calculations and statistical correlations for oligo-probes design. Nucleic Acids Res 31:4211–4217PubMedCentralPubMedGoogle Scholar
  212. McKay RA, Miraglia LJ, Cummins LL, Owens SR, Sasmor H, Dean NM (1999) Characterization of a potent and specific class of antisense oligonucleotide inhibitor of human protein kinase C-alpha expression. J Biol Chem 274:1715–1722PubMedGoogle Scholar
  213. McMahon BM, Mays D, Lipsky J, Stewart JA, Fauq A, Richelson E (2002) Pharmacokinetics and tissue distribution of a peptide nucleic acid after intravenous administration. Antisense Nucleic Acid Drug Dev 12:65–70PubMedGoogle Scholar
  214. McManus CJ, Graveley BR (2011) RNA structure and the mechanisms of alternative splicing. Curr Opin Genet Dev 21:373–379PubMedCentralPubMedGoogle Scholar
  215. McSwiggen J (2013) Specific gene activation by disruption of PRC2-lncRNA interactions. In The Eighteenth Annual Meeting of the RNA Society, abstract 130Google Scholar
  216. Meister G, Landthaler M, Dorsett Y, Tuschl T (2004) Sequence-specific inhibition of microRNA- and siRNA-induced RNA silencing. RNA 10:544–550PubMedCentralPubMedGoogle Scholar
  217. Meister G, Tuschl T (2004) Mechanisms of gene silencing by double-stranded RNA. Nature 431:343–349PubMedGoogle Scholar
  218. Merideth MA, Gordon LB, Clauss S, Sachdev V, Smith AC, Perry MB, Brewer CC, Zalewski C, Kim HJ, Solomon B et al (2008) Phenotype and course of Hutchinson-Gilford progeria syndrome. N Engl J Med 358:592–604PubMedCentralPubMedGoogle Scholar
  219. Meyer K, Marquis J, Trub J, Nlend Nlend R, Verp S, Ruepp MD, Imboden H, Barde I, Trono D, Schumperli D (2009) Rescue of a severe mouse model for spinal muscular atrophy by U7 snRNA-mediated splicing modulation. Hum Mol Genet 18:546–555PubMedGoogle Scholar
  220. Meyer KD, Saletore Y, Zumbo P, Elemento O, Mason CE, Jaffrey SR (2012) Comprehensive analysis of mRNA methylation reveals enrichment in 3′ UTRs and near stop codons. Cell 149:1635–1646PubMedCentralPubMedGoogle Scholar
  221. Michele DE, Barresi R, Kanagawa M, Saito F, Cohn RD, Satz JS, Dollar J, Nishino I, Kelley RI, Somer H et al (2002) Post-translational disruption of dystroglycan-ligand interactions in congenital muscular dystrophies. Nature 418:417–422PubMedGoogle Scholar
  222. Miller JW, Urbinati CR, Teng-Umnuay P, Stenberg MG, Byrne BJ, Thornton CA, Swanson MS (2000) Recruitment of human muscleblind proteins to (CUG)(n) expansions associated with myotonic dystrophy. EMBO J 19:4439–4448PubMedCentralPubMedGoogle Scholar
  223. Ming X, Carver K, Fisher M, Noel R, Cintrat JC, Gillet D, Barbier J, Cao C, Bauman J, Juliano RL (2013) The small molecule Retro-1 enhances the pharmacological actions of antisense and splice switching oligonucleotides. Nucleic Acids Res 41:3673–3687PubMedCentralPubMedGoogle Scholar
  224. Miraglia L, Watt AT, Graham MJ, Crooke ST (2000) Variations in mRNA content have no effect on the potency of antisense oligonucleotides. Antisense Nucleic Acid Drug Dev 10:453–461PubMedGoogle Scholar
  225. Mitrpant C, Porensky P, Zhou H, Price L, Muntoni F, Fletcher S, Wilton SD, Burghes AH (2013) Improved antisense oligonucleotide design to suppress aberrant SMN2 gene transcript processing: towards a treatment for spinal muscular atrophy. PLoS One 8:e62114PubMedCentralPubMedGoogle Scholar
  226. Miyajima H, Miyaso H, Okumura M, Kurisu J, Imaizumi K (2002) Identification of a cis-acting element for the regulation of SMN exon 7 splicing. J Biol Chem 277:23271–23277PubMedGoogle Scholar
  227. Mizrahi RA, Schirle NT, Beal PA (2013) Potent and selective inhibition of A-to-I RNA editing with 2′-O-methyl/locked nucleic acid-containing antisense oligoribonucleotides. ACS Chem Biol 8:832–839PubMedCentralPubMedGoogle Scholar
  228. Modarresi F, Faghihi MA, Lopez-Toledano MA, Fatemi RP, Magistri M, Brothers SP, van der Brug MP, Wahlestedt C (2012) Inhibition of natural antisense transcripts in vivo results in gene-specific transcriptional upregulation. Nat Biotechnol 30:453–459PubMedCentralPubMedGoogle Scholar
  229. Monani UR, Lorson CL, Parsons DW, Prior TW, Androphy EJ, Burghes AH, McPherson JD (1999) A single nucleotide difference that alters splicing patterns distinguishes the SMA gene SMN1 from the copy gene SMN2. Hum Mol Genet 8:1177–1183PubMedGoogle Scholar
  230. Monani UR, Sendtner M, Coovert DD, Parsons DW, Andreassi C, Le TT, Jablonka S, Schrank B, Rossoll W, Prior TW et al (2000) The human centromeric survival motor neuron gene (SMN2) rescues embryonic lethality in Smn(−/−) mice and results in a mouse with spinal muscular atrophy. Hum Mol Genet 9:333–339PubMedGoogle Scholar
  231. Monia BP, Johnston JF, Ecker DJ, Zounes MA, Lima WF, Freier SM (1992) Selective inhibition of mutant Ha-ras mRNA expression by antisense oligonucleotides. J Biol Chem 267:19954–19962PubMedGoogle Scholar
  232. Monia BP, Lesnik EA, Gonzalez C, Lima WF, McGee D, Guinosso CJ, Kawasaki AM, Cook PD, Freier SM (1993) Evaluation of 2'-modified oligonucleotides containing 2′-deoxy gaps as antisense inhibitors of gene expression. J Biol Chem 268:14514–14522PubMedGoogle Scholar
  233. Mordes D, Luo X, Kar A, Kuo D, Xu L, Fushimi K, Yu G, Sternberg P Jr, Wu JY (2006) Pre-mRNA splicing and retinitis pigmentosa. Mol Vis 12:1259–1271PubMedCentralPubMedGoogle Scholar
  234. Morris KV, Chan SW, Jacobsen SE, Looney DJ (2004) Small interfering RNA-induced transcriptional gene silencing in human cells. Science 305:1289–1292PubMedGoogle Scholar
  235. Morris KV, Santoso S, Turner AM, Pastori C, Hawkins PG (2008) Bidirectional transcription directs both transcriptional gene activation and suppression in human cells. PLoS Genet 4:e1000258PubMedCentralPubMedGoogle Scholar
  236. Morrow JR, Iranzo O (2004) Synthetic metallonucleases for RNA cleavage. Curr Opin Chem Biol 8:192–200PubMedGoogle Scholar
  237. Moulton HM, Moulton JD (2010) Morpholinos and their peptide conjugates: therapeutic promise and challenge for Duchenne muscular dystrophy. Biochim Biophys Acta 1798:2296–2303PubMedGoogle Scholar
  238. Moulton JD, Jiang S (2009) Gene knockdowns in adult animals: PPMOs and vivo-morpholinos. Molecules 14:1304–1323PubMedGoogle Scholar
  239. Mulders SA, van den Broek WJ, Wheeler TM, Croes HJ, van Kuik-Romeijn P, de Kimpe SJ, Furling D, Platenburg GJ, Gourdon G, Thornton CA et al (2009) Triplet-repeat oligonucleotide-mediated reversal of RNA toxicity in myotonic dystrophy. Proc Natl Acad Sci U S A 106:13915–13920PubMedCentralPubMedGoogle Scholar
  240. Muntoni F, Wood MJ (2011) Targeting RNA to treat neuromuscular disease. Nat Rev Drug Discov 10:621–637PubMedGoogle Scholar
  241. Murray S, Ittig D, Koller E, Berdeja A, Chappell A, Prakash TP, Norrbom M, Swayze EE, Leumann CJ, Seth PP (2012) TricycloDNA-modified oligo-2′-deoxyribonucleotides reduce scavenger receptor B1 mRNA in hepatic and extra-hepatic tissues–a comparative study of oligonucleotide length, design and chemistry. Nucleic Acids Res 40:6135–6143PubMedCentralPubMedGoogle Scholar
  242. Nakamori M, Gourdon G, Thornton CA (2011) Stabilization of expanded (CTG)*(CAG) repeats by antisense oligonucleotides. Mol Ther: J Am Soc Gene Ther 19:2222–2227Google Scholar
  243. Napoli S, Pastori C, Magistri M, Carbone GM, Catapano CV (2009) Promoter-specific transcriptional interference and c-myc gene silencing by siRNAs in human cells. EMBO J 28:1708–1719PubMedCentralPubMedGoogle Scholar
  244. Nilsen TW, Graveley BR (2010) Expansion of the eukaryotic proteome by alternative splicing. Nature 463:457–463PubMedCentralPubMedGoogle Scholar
  245. Obad S, dos Santos CO, Petri A, Heidenblad M, Broom O, Ruse C, Fu C, Lindow M, Stenvang J, Straarup EM et al (2011) Silencing of microRNA families by seed-targeting tiny LNAs. Nat Genet 43:371–378PubMedCentralPubMedGoogle Scholar
  246. Orban TI, Izaurralde E (2005) Decay of mRNAs targeted by RISC requires XRN1, the Ski complex, and the exosome. RNA 11:459–469PubMedCentralPubMedGoogle Scholar
  247. Orengo JP, Chambon P, Metzger D, Mosier DR, Snipes GJ, Cooper TA (2008) 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 U S A 105:2646–2651PubMedCentralPubMedGoogle Scholar
  248. Osborne RJ, Lin X, Welle S, Sobczak K, O’Rourke JR, Swanson MS, Thornton CA (2009) Transcriptional and post-transcriptional impact of toxic RNA in myotonic dystrophy. Hum Mol Genet 18:1471–1481PubMedCentralPubMedGoogle Scholar
  249. Osman EY, Yen PF, Lorson CL (2012) Bifunctional RNAs targeting the intronic splicing silencer N1 increase SMN levels and reduce disease severity in an animal model of spinal muscular atrophy. Mol Ther: J Am Soc Gene Ther 20:119–126Google Scholar
  250. Osorio FG, Navarro CL, Cadinanos J, Lopez-Mejia IC, Quiros PM, Bartoli C, Rivera J, Tazi J, Guzman G, Varela I et al (2011) Splicing-directed therapy in a new mouse model of human accelerated aging. Sci Transl Med 3:106ra107PubMedGoogle Scholar
  251. Ouyang XM, Yan D, Du LL, Hejtmancik JF, Jacobson SG, Nance WE, Li AR, Angeli S, Kaiser M, Newton V et al (2005) Characterization of Usher syndrome type I gene mutations in an Usher syndrome patient population. Hum Genet 116:292–299PubMedGoogle Scholar
  252. Overington JP, Al-Lazikani B, Hopkins AL (2006) How many drug targets are there? Nat Rev Drug Discov 5:993–996PubMedGoogle Scholar
  253. Padgett RA (2012) New connections between splicing and human disease. Trends Genet 28:147–154PubMedCentralPubMedGoogle Scholar
  254. Pallan PS, Greene EM, Jicman PA, Pandey RK, Manoharan M, Rozners E, Egli M (2011) Unexpected origins of the enhanced pairing affinity of 2′-fluoro-modified RNA. Nucleic Acids Res 39:3482–3495PubMedCentralPubMedGoogle Scholar
  255. Passini MA, Bu J, Richards AM, Kinnecom C, Sardi SP, Stanek LM, Hua Y, Rigo F, Matson J, Hung G et al (2011) Antisense oligonucleotides delivered to the mouse CNS ameliorate symptoms of severe spinal muscular atrophy. Sci Transl Med 3:72ra18PubMedCentralPubMedGoogle Scholar
  256. Patel DJ, Ma JB, Yuan YR, Ye K, Pei Y, Kuryavyi V, Malinina L, Meister G, Tuschl T (2006) Structural biology of RNA silencing and its functional implications. Cold Spring Harb Symp Quant Biol 71:81–93PubMedGoogle Scholar
  257. Peacey E, Rodriguez L, Liu Y, Wolfe MS (2012) Targeting a pre-mRNA structure with bipartite antisense molecules modulates tau alternative splicing. Nucleic Acids Res 40:9836–9849PubMedCentralPubMedGoogle Scholar
  258. Peng CG, Damha MJ (2008) Probing DNA polymerase activity with stereoisomeric 2′-fluoro-β-D-arabinose (2′F-araNTPs) and 2′-fluoro-β-D-ribose (2′F-rNTPs) nucleoside 5′-triphosphates. Can J Chem 86:881–891Google Scholar
  259. Peng Z, Cheng Y, Tan BC, Kang L, Tian Z, Zhu Y, Zhang W, Liang Y, Hu X, Tan X et al (2012) Comprehensive analysis of RNA-Seq data reveals extensive RNA editing in a human transcriptome. Nat Biotechnol 30:253–260PubMedGoogle Scholar
  260. Perales R, Bentley D (2009) “Cotranscriptionality”: the transcription elongation complex as a nexus for nuclear transactions. Mol Cell 36:178–191PubMedCentralPubMedGoogle Scholar
  261. Petit C (2001) Usher syndrome: from genetics to pathogenesis. Annu Rev Genomics Hum Genet 2:271–297PubMedGoogle Scholar
  262. Place RF, Li LC, Pookot D, Noonan EJ, Dahiya R (2008) MicroRNA-373 induces expression of genes with complementary promoter sequences. Proc Natl Acad Sci U S A 105:1608–1613PubMedCentralPubMedGoogle Scholar
  263. Polymenidou M, Lagier-Tourenne C, Hutt KR, Bennett CF, Cleveland DW, Yeo GW (2012) Misregulated RNA processing in amyotrophic lateral sclerosis. Brain Res 1462:3–15PubMedCentralPubMedGoogle Scholar
  264. Porensky PN, Mitrpant C, McGovern VL, Bevan AK, Foust KD, Kaspar BK, Wilton SD, Burghes AH (2011) A single administration of morpholino antisense oligomer rescues spinal muscular atrophy in mouse. Hum Mol Genet 21(7):1625–1638PubMedCentralPubMedGoogle Scholar
  265. Prakash TP (2011) An overview of sugar-modified oligonucleotides for antisense therapeutics. Chem Biodivers 8:1616–1641PubMedGoogle Scholar
  266. Prasanth KV, Prasanth SG, Xuan Z, Hearn S, Freier SM, Bennett CF, Zhang MQ, Spector DL (2005) Regulating gene expression through RNA nuclear retention. Cell 123:249–263PubMedGoogle Scholar
  267. Preker P, Nielsen J, Schierup MH, Jensen TH (2009) RNA polymerase plays both sides: vivid and bidirectional transcription around and upstream of active promoters. Cell Cycle 8:1106–1107PubMedGoogle Scholar
  268. Prior TW, Krainer AR, Hua Y, Swoboda KJ, Snyder PC, Bridgeman SJ, Burghes AH, Kissel JT (2009) A positive modifier of spinal muscular atrophy in the SMN2 gene. Am J Hum Genet 85:408–413PubMedCentralPubMedGoogle Scholar
  269. Prior TW, Swoboda KJ, Scott HD, Hejmanowski AQ (2004) Homozygous SMN1 deletions in unaffected family members and modification of the phenotype by SMN2. Am J Med Genet A 130A:307–310PubMedGoogle Scholar
  270. Proudfoot NJ (2011) Ending the message: poly(A) signals then and now. Genes Dev 25:1770–1782PubMedCentralPubMedGoogle Scholar
  271. Qureshi IA, Mattick JS, Mehler MF (2010) Long non-coding RNAs in nervous system function and disease. Brain Res 1338:20–35PubMedGoogle Scholar
  272. Rajeev KG, Zimmermann T, Manoharan M, Maier M, Kuchimanchi S, Charisse K (2013) Small interfering RNAs targeting transthyretin mRNA for treatment of transthyretin-associated diseases (Alnylam Pharmaceuticals, USA), WO2013075035A1Google Scholar
  273. Ranum LP, Cooper TA (2006) RNA-mediated neuromuscular disorders. Annu Rev Neurosci 29:259–277PubMedGoogle Scholar
  274. Ray D, Kazan H, Cook KB, Weirauch MT, Najafabadi HS, Li X, Gueroussov S, Albu M, Zheng H, Yang A et al (2013) A compendium of RNA-binding motifs for decoding gene regulation. Nature 499:172–177PubMedCentralPubMedGoogle Scholar
  275. Renton AE, Majounie E, Waite A, Simon-Sanchez J, Rollinson S, Gibbs JR, Schymick JC, Laaksovirta H, van Swieten JC, Myllykangas L et al (2011) A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 72:257–268PubMedCentralPubMedGoogle Scholar
  276. Rettig GR, Behlke MA (2012) Progress toward in vivo use of siRNAs-II. Mol Ther: J Am Soc Gene Ther 20:483–512Google Scholar
  277. Rigo F, Hua Y, Chun SJ, Prakash TP, Krainer AR, Bennett CF (2012a) Synthetic oligonucleotides recruit ILF2/3 to RNA transcripts to modulate splicing. Nat Chem Biol 8:555–561PubMedGoogle Scholar
  278. Rigo F, Hua Y, Krainer AR, Bennett CF (2012b) Antisense-based therapy for the treatment of spinal muscular atrophy. J Cell Biol 199:21–25PubMedCentralPubMedGoogle Scholar
  279. Riguet E, Tripathi S, Chaubey B, Desire J, Pandey VN, Decout JL (2004) A peptide nucleic acid-neamine conjugate that targets and cleaves HIV-1 TAR RNA inhibits viral replication. J Med Chem 47:4806–4809PubMedGoogle Scholar
  280. Rinn JL, Chang HY (2012) Genome regulation by long noncoding RNAs. Annu Rev Biochem 81:145–166PubMedGoogle Scholar
  281. Rochette CF, Gilbert N, Simard LR (2001) SMN gene duplication and the emergence of the SMN2 gene occurred in distinct hominids: SMN2 is unique to Homo sapiens. Hum Genet 108:255–266PubMedGoogle Scholar
  282. Sahay G, Querbes W, Alabi C, Eltoukhy A, Sarkar S, Zurenko C, Karagiannis E, Love K, Chen D, Zoncu R et al (2013) Efficiency of siRNA delivery by lipid nanoparticles is limited by endocytic recycling. Nat Biotechnol 31:653–658PubMedGoogle Scholar
  283. Sarma K, Levasseur P, Aristarkhov A, Lee JT (2010) Locked nucleic acids (LNAs) reveal sequence requirements and kinetics of Xist RNA localization to the X chromosome. Proc Natl Acad Sci U S A 107:22196–22201PubMedCentralPubMedGoogle Scholar
  284. Sazani P, Gemignani F, Kang SH, Maier MA, Manoharan M, Persmark M, Bortner D, Kole R (2002) Systemically delivered antisense oligomers upregulate gene expression in mouse tissues. Nat Biotechnol 20:1228–1233PubMedGoogle Scholar
  285. Sazani P, Graziewicz MA, Kole R (2007) Splice switching oligonucleotides as potential therapeutics. In: Crooke ST (ed) Antisense drug technology: principles, strategies, and applications. CRC, Boca Raton, FL, pp 89–114Google Scholar
  286. Scaffidi P, Misteli T (2005) Reversal of the cellular phenotype in the premature aging disease Hutchinson-Gilford progeria syndrome. Nat Med 11:440–445PubMedCentralPubMedGoogle Scholar
  287. Schoenberg DR, Maquat LE (2012) Regulation of cytoplasmic mRNA decay. Nat Rev Genet 13:246–259PubMedCentralPubMedGoogle Scholar
  288. Schreml J, Riessland M, Paterno M, Garbes L, Rossbach K, Ackermann B, Kramer J, Somers E, Parson SH, Heller R et al (2012) Severe SMA mice show organ impairment that cannot be rescued by therapy with the HDACi JNJ-26481585. Eur J Human Genet 21(6):643–652Google Scholar
  289. Schwartz JC, Younger ST, Nguyen NB, Hardy DB, Monia BP, Corey DR, Janowski BA (2008) Antisense transcripts are targets for activating small RNAs. Nat Struct Mol Biol 15:842–848PubMedCentralPubMedGoogle Scholar
  290. Schweingruber C, Rufener SC, Zund D, Yamashita A, Muhlemann O (2013) Nonsense-mediated mRNA decay—mechanisms of substrate mRNA recognition and degradation in mammalian cells. Biochim Biophys Acta 1829:612–623PubMedGoogle Scholar
  291. Seila AC, Core LJ, Lis JT, Sharp PA (2009) Divergent transcription: a new feature of active promoters. Cell Cycle 8:2557–2564PubMedGoogle Scholar
  292. Senn JJ, Burel S, Henry SP (2005) Non-CpG-containing antisense 2′-methoxyethyl oligonucleotides activate a proinflammatory response independent of Toll-like receptor 9 or myeloid differentiation factor 88. J Pharmacol Exp Ther 314:972–979PubMedGoogle Scholar
  293. Seow Y, Sibley CR, Wood MJ (2012) Artificial mirtron-mediated gene knockdown: functional DMPK silencing in mammalian cells. RNA 18:1328–1337PubMedCentralPubMedGoogle Scholar
  294. Seth PP, Allerson CR, Berdeja A, Siwkowski A, Pallan PS, Gaus H, Prakash TP, Watt AT, Egli M, Swayze EE (2010) An exocyclic methylene group acts as a bioisostere of the 2′-oxygen atom in LNA. J Am Chem Soc 132:14942–14950PubMedCentralPubMedGoogle Scholar
  295. Seth PP, Jazayeri A, Yu J, Allerson CR, Bhat B, Swayze EE (2012a) Structure activity relationships of alpha-L-LNA modified phosphorothioate gapmer antisense oligonucleotides in animals. Mol Ther Nucleic Acids 1:e47PubMedCentralPubMedGoogle Scholar
  296. Seth PP, Siwkowski A, Allerson CR, Vasquez G, Lee S, Prakash TP, Wancewicz EV, Witchell D, Swayze EE (2009) Short antisense oligonucleotides with novel 2′-4′ conformationally restricted nucleoside analogues show improved potency without increased toxicity in animals. J Med Chem 52:10–13PubMedGoogle Scholar
  297. Seth PP, Yu J, Jazayeri A, Pallan PS, Allerson CR, Ostergaard ME, Liu F, Herdewijn P, Egli M, Swayze EE (2012b) Synthesis and antisense properties of fluoro cyclohexenyl nucleic acid (F-CeNA), a nuclease stable mimic of 2′-fluoro RNA. J Org Chem 77:5074–5085PubMedCentralPubMedGoogle Scholar
  298. Seznec H, Agbulut O, Sergeant N, Savouret C, Ghestem A, Tabti N, Willer JC, Ourth L, Duros C, Brisson E et al (2001) Mice transgenic for the human myotonic dystrophy region with expanded CTG repeats display muscular and brain abnormalities. Hum Mol Genet 10:2717–2726PubMedGoogle Scholar
  299. Shababi M, Habibi J, Yang HT, Vale SM, Sewell WA, Lorson CL (2010) Cardiac defects contribute to the pathology of spinal muscular atrophy models. Hum Mol Genet 19:4059–4071PubMedGoogle Scholar
  300. Shababi M, Lorson CL, Rudnik-Schoneborn SS (2013) Spinal muscular atrophy: a motor neuron disorder or a multi-organ disease? J Anat 224(1):15–28PubMedGoogle Scholar
  301. Shatkin AJ, Manley JL (2000) The ends of the affair: capping and polyadenylation. Nat Struct Biol 7:838–842PubMedGoogle Scholar
  302. Sheehan JP, Phan TM (2001) Phosphorothioate oligonucleotides inhibit the intrinsic tenase complex by an allosteric mechanism. Biochemistry 40:4980–4989PubMedGoogle Scholar
  303. Shibahara S, Mukai S, Nishihara T, Inoue H, Ohtsuka E, Morisawa H (1987) Site-directed cleavage of RNA. Nucleic Acids Res 15:4403–4415PubMedCentralPubMedGoogle Scholar
  304. Sierakowska H, Sambade MJ, Agrawal S, Kole R (1996) Repair of thalassemic human beta-globin mRNA in mammalian cells by antisense oligonucleotides. Proc Natl Acad Sci U S A 93:12840–12844PubMedCentralPubMedGoogle Scholar
  305. Singh NK, Singh NN, Androphy EJ, Singh RN (2006) 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 26:1333–1346PubMedCentralPubMedGoogle Scholar
  306. Sipes TB, Freier SM (2008) Prediction of antisense oligonucleotide efficacy using aggregate motifs. J Bioinform Comput Biol 6:919–932PubMedGoogle Scholar
  307. Siwkowski AM, Malik L, Esau CC, Maier MA, Wancewicz EV, Albertshofer K, Monia BP, Bennett CF, Eldrup AB (2004) Identification and functional validation of PNAs that inhibit murine CD40 expression by redirection of splicing. Nucleic Acids Res 32:2695–2706PubMedCentralPubMedGoogle Scholar
  308. Skordis LA, Dunckley MG, Yue B, Eperon IC, Muntoni F (2003) Bifunctional antisense oligonucleotides provide a trans-acting splicing enhancer that stimulates SMN2 gene expression in patient fibroblasts. Proc Natl Acad Sci U S A 100:4114–4119PubMedCentralPubMedGoogle Scholar
  309. Smith RA, Miller TM, Yamanaka K, Monia BP, Condon TP, Hung G, Lobsiger CS, Ward CM, McAlonis-Downes M, Wei H et al (2006) Antisense oligonucleotide therapy for neurodegenerative disease. J Clin Invest 116:2290–2296PubMedCentralPubMedGoogle Scholar
  310. Sobczak K, Wheeler TM, Wang W, Thornton CA (2013) RNA interference targeting CUG repeats in a mouse model of myotonic dystrophy. Mol Ther: J Am Soc Gene Ther 21:380–387Google Scholar
  311. Spitali P, Aartsma-Rus A (2012) Splice modulating therapies for human disease. Cell 148:1085–1088PubMedGoogle Scholar
  312. Squires JE, Patel HR, Nousch M, Sibbritt T, Humphreys DT, Parker BJ, Suter CM, Preiss T (2012) Widespread occurrence of 5-methylcytosine in human coding and non-coding RNA. Nucleic Acids Res 40:5023–5033PubMedCentralPubMedGoogle Scholar
  313. Stein CA, Hansen JB, Lai J, Wu S, Voskresenskiy A, Hog A, Worm J, Hedtjarn M, Souleimanian N, Miller P et al (2010) Efficient gene silencing by delivery of locked nucleic acid antisense oligonucleotides, unassisted by transfection reagents. Nucleic Acids Res 38:e3PubMedCentralPubMedGoogle Scholar
  314. Straarup EM, Fisker N, Hedtjarn M, Lindholm MW, Rosenbohm C, Aarup V, Hansen HF, Orum H, Hansen JB, Koch T (2010) Short locked nucleic acid antisense oligonucleotides potently reduce apolipoprotein B mRNA and serum cholesterol in mice and non-human primates. Nucleic Acids Res 38:7100–7111PubMedCentralPubMedGoogle Scholar
  315. Swayze EE, Bhat B (2007) The medicinal chemistry of oligonucleotides. In: Crooke ST (ed) Antisense drug technology: principles, strategies, and applications. CRC, Boca Raton, FL, pp 143–182Google Scholar
  316. Swayze EE, Siwkowski AM, Wancewicz EV, Migawa MT, Wyrzykiewicz TK, Hung G, Monia BP, Bennett CF (2007) Antisense oligonucleotides containing locked nucleic acid improve potency but cause significant hepatotoxicity in animals. Nucleic Acids Res 35:687–700PubMedCentralPubMedGoogle Scholar
  317. Taneja KL, McCurrach M, Schalling M, Housman D, Singer RH (1995) Foci of trinucleotide repeat transcripts in nuclei of myotonic dystrophy cells and tissues. J Cell Biol 128:995–1002PubMedGoogle Scholar
  318. Taniguchi-Ikeda M, Kobayashi K, Kanagawa M, Yu CC, Mori K, Oda T, Kuga A, Kurahashi H, Akman HO, DiMauro S et al (2011) Pathogenic exon-trapping by SVA retrotransposon and rescue in Fukuyama muscular dystrophy. Nature 478:127–131PubMedCentralPubMedGoogle Scholar
  319. Tazi J, Bakkour N, Stamm S (2009) Alternative splicing and disease. Biochim Biophys Acta 1792:14–26PubMedGoogle Scholar
  320. Teplova M, Minasov G, Tereshko V, Inamati GB, Cook PD, Manoharan M, Egli M (1999) Crystal structure and improved antisense properties of 2′-O-(2-methoxyethyl)-RNA. Nat Struct Biol 6:535–539PubMedGoogle Scholar
  321. Toda T, Kobayashi K (1999) Fukuyama-type congenital muscular dystrophy: the first human disease to be caused by an ancient retrotransposal integration. J Mol Med 77:816–823PubMedGoogle Scholar
  322. Tripathi V, Ellis JD, Shen Z, Song DY, Pan Q, Watt AT, Freier SM, Bennett CF, Sharma A, Bubulya PA et al (2010) The nuclear-retained noncoding RNA MALAT1 regulates alternative splicing by modulating SR splicing factor phosphorylation. Mol Cell 39:925–938PubMedGoogle Scholar
  323. Turner, A.M., and Morris, K.V. (2010). Controlling transcription with noncoding RNAs in mammalian cells. Biotechniques 48, ix-xvi.Google Scholar
  324. Ulitsky I, Bartel DP (2013) lincRNAs: genomics, evolution, and mechanisms. Cell 154:26–46PubMedCentralPubMedGoogle Scholar
  325. Usman N, Blatt LM (2000) Nuclease-resistant synthetic ribozymes: developing a new class of therapeutics. J Clin Invest 106:1197–1202PubMedCentralPubMedGoogle Scholar
  326. Vaishnaw AK, Gollob J, Gamba-Vitalo C, Hutabarat R, Sah D, Meyers R, de Fougerolles T, Maraganore J (2010) A status report on RNAi therapeutics. Silence 1:14PubMedCentralPubMedGoogle Scholar
  327. Valori CF, Ning K, Wyles M, Mead RJ, Grierson AJ, Shaw PJ, Azzouz M (2010) Systemic delivery of scAAV9 expressing SMN prolongs survival in a model of spinal muscular atrophy. Sci Transl Med 2:35ra42PubMedGoogle Scholar
  328. van Deutekom JC, Janson AA, Ginjaar IB, Frankhuizen WS, Aartsma-Rus A, Bremmer-Bout M, den Dunnen JT, Koop K, van der Kooi AJ, Goemans NM et al (2007) Local dystrophin restoration with antisense oligonucleotide PRO051. N Engl J Med 357:2677–2686PubMedGoogle Scholar
  329. Verpy E, Leibovici M, Zwaenepoel I, Liu XZ, Gal A, Salem N, Mansour A, Blanchard S, Kobayashi I, Keats BJ et al (2000) A defect in harmonin, a PDZ domain-containing protein expressed in the inner ear sensory hair cells, underlies Usher syndrome type 1C. Nat Genet 26:51–55PubMedGoogle Scholar
  330. Vester B, Wengel J (2004) LNA (locked nucleic acid): high-affinity targeting of complementary RNA and DNA. Biochemistry 43:13233–13241PubMedGoogle Scholar
  331. Vezain M, Saugier-Veber P, Goina E, Touraine R, Manel V, Toutain A, Fehrenbach S, Frebourg T, Pagani F, Tosi M et al (2010) A rare SMN2 variant in a previously unrecognized composite splicing regulatory element induces exon 7 inclusion and reduces the clinical severity of spinal muscular atrophy. Hum Mutat 31:E1110–E1125PubMedGoogle Scholar
  332. Vickers T, Baker BF, Cook PD, Zounes M, Buckheit RW Jr, Germany J, Ecker DJ (1991) Inhibition of HIV-LTR gene expression by oligonucleotides targeted to the TAR element. Nucleic Acids Res 19:3359–3368PubMedCentralPubMedGoogle Scholar
  333. Vickers TA, Crooke ST (2012) siRNAs targeted to certain polyadenylation sites promote specific, RISC-independent degradation of messenger RNAs. Nucleic Acids Res 40(13):6223–6234PubMedCentralPubMedGoogle Scholar
  334. Vickers TA, Koo S, Bennett CF, Crooke ST, Dean NM, Baker BF (2003) Efficient reduction of target RNAs by small interfering RNA and RNase H-dependent antisense agents. A comparative analysis. J Biol Chem 278:7108–7118PubMedGoogle Scholar
  335. Vickers TA, Wyatt JR, Burckin T, Bennett CF, Freier SM (2001) Fully modified 2′ MOE oligonucleotides redirect polyadenylation. Nucleic Acids Res 29:1293–1299PubMedCentralPubMedGoogle Scholar
  336. Vickers TA, Wyatt JR, Freier SM (2000) Effects of RNA secondary structure on cellular antisense activity. Nucleic Acids Res 28:1340–1347PubMedCentralPubMedGoogle Scholar
  337. Villemaire J, Dion I, Elela SA, Chabot B (2003) Reprogramming alternative pre-messenger RNA splicing through the use of protein-binding antisense oligonucleotides. J Biol Chem 278: 50031–50039PubMedGoogle Scholar
  338. Vitiello D, Pecchia DB, Burke JM (2000) Intracellular ribozyme-catalyzed trans-cleavage of RNA monitored by fluorescence resonance energy transfer. RNA 6:628–637PubMedCentralPubMedGoogle Scholar
  339. Vitte JM, Davoult B, Roblot N, Mayer M, Joshi V, Courageot S, Tronche F, Vadrot J, Moreau MH, Kemeny F et al (2004) Deletion of murine Smn exon 7 directed to liver leads to severe defect of liver development associated with iron overload. Am J Pathol 165:1731–1741PubMedCentralPubMedGoogle Scholar
  340. Voigt T, Meyer K, Baum O, Schumperli D (2010) Ultrastructural changes in diaphragm neuromuscular junctions in a severe mouse model for Spinal Muscular Atrophy and their prevention by bifunctional U7 snRNA correcting SMN2 splicing. Neuromuscul Disord 20:744–752PubMedGoogle Scholar
  341. Vorlova S, Rocco G, Lefave CV, Jodelka FM, Hess K, Hastings ML, Henke E, Cartegni L (2011) Induction of antagonistic soluble decoy receptor tyrosine kinases by intronic polya activation. Mol Cell 43:927–939PubMedCentralPubMedGoogle Scholar
  342. Wahlestedt C (2013) Targeting long non-coding RNA to therapeutically upregulate gene expression. Nat Rev Drug Discov 12:433–446PubMedGoogle Scholar
  343. Wan L, Battle DJ, Yong J, Gubitz AK, Kolb SJ, Wang J, Dreyfuss G (2005) The survival of motor neurons protein determines the capacity for snRNP assembly: biochemical deficiency in spinal muscular atrophy. Mol Cell Biol 25:5543–5551PubMedCentralPubMedGoogle Scholar
  344. Wan Y, Kertesz M, Spitale RC, Segal E, Chang HY (2011) Understanding the transcriptome through RNA structure. Nat Rev Genet 12:641–655PubMedGoogle Scholar
  345. Wancewicz EV, Maier MA, Siwkowski AM, Albertshofer K, Winger TM, Berdeja A, Gaus H, Vickers TA, Bennett CF, Monia BP et al (2010) Peptide nucleic acids conjugated to short basic peptides show improved pharmacokinetics and antisense activity in adipose tissue. J Med Chem 53:3919–3926PubMedCentralPubMedGoogle Scholar
  346. Wang GS, Cooper TA (2007) Splicing in disease: disruption of the splicing code and the decoding machinery. Nat Rev Genet 8:749–761PubMedGoogle Scholar
  347. Ward AJ, Rimer M, Killian JM, Dowling JJ, Cooper TA (2010) CUGBP1 overexpression in mouse skeletal muscle reproduces features of myotonic dystrophy type 1. Hum Mol Genet 19: 3614–3622PubMedCentralPubMedGoogle Scholar
  348. Watanabe TA, Geary RS, Levin AA (2006) Plasma protein binding of an antisense oligonucleotide targeting human ICAM-1 (ISIS 2302). Oligonucleotides 16:169–180PubMedGoogle Scholar
  349. Weismann D, Erion DM, Ignatova-Todorava I, Nagai Y, Stark R, Hsiao JJ, Flannery C, Birkenfeld AL, May T, Kahn M et al (2011) Knockdown of the gene encoding Drosophila tribbles homologue 3 (Trib3) improves insulin sensitivity through peroxisome proliferator-activated receptor-gamma (PPAR-gamma) activation in a rat model of insulin resistance. Diabetologia 54: 935–944PubMedCentralPubMedGoogle Scholar
  350. Wheeler TM, Leger AJ, Pandey SK, MacLeod AR, Nakamori M, Cheng SH, Wentworth BM, Bennett CF, Thornton CA (2012) Targeting nuclear RNA for in vivo correction of myotonic dystrophy. Nature 488:111–115PubMedGoogle Scholar
  351. Wheeler TM, Lueck JD, Swanson MS, Dirksen RT, Thornton CA (2007) Correction of ClC-1 splicing eliminates chloride channelopathy and myotonia in mouse models of myotonic dystrophy. J Clin Invest 117:3952–3957PubMedCentralPubMedGoogle Scholar
  352. Wheeler TM, Sobczak K, Lueck JD, Osborne RJ, Lin X, Dirksen RT, Thornton CA (2009) Reversal of RNA dominance by displacement of protein sequestered on triplet repeat RNA. Science 325:336–339PubMedCentralPubMedGoogle Scholar
  353. Williams JH, Schray RC, Patterson CA, Ayitey SO, Tallent MK, Lutz GJ (2009) Oligonucleotide-mediated survival of motor neuron protein expression in CNS improves phenotype in a mouse model of spinal muscular atrophy. J Neurosci 29:7633–7638PubMedGoogle Scholar
  354. Wilusz JE, Devanney SC, Caputi M (2005) Chimeric peptide nucleic acid compounds modulate splicing of the bcl-x gene in vitro and in vivo. Nucleic Acids Res 33:6547–6554PubMedCentralPubMedGoogle Scholar
  355. Wooddell CI, Rozema DB, Hossbach M, John M, Hamilton HL, Chu Q, Hegge JO, Klein JJ, Wakefield DH, Oropeza CE et al (2013) Hepatocyte-targeted RNAi therapeutics for the treatment of chronic hepatitis B virus infection. Mol Ther: J Am Soc Gene Ther 21:973–985Google Scholar
  356. Woolf TM, Chase JM, Stinchcomb DT (1995) Toward the therapeutic editing of mutated RNA sequences. Proc Natl Acad Sci U S A 92:8298–8302PubMedCentralPubMedGoogle Scholar
  357. Worman HJ, Fong LG, Muchir A, Young SG (2009) Laminopathies and the long strange trip from basic cell biology to therapy. J Clin Invest 119:1825–1836PubMedCentralPubMedGoogle Scholar
  358. Wu H, Lima WF, Zhang H, Fan A, Sun H, Crooke ST (2004) Determination of the role of the human RNase H1 in the pharmacology of DNA-like antisense drugs. J Biol Chem 279:17181–17189PubMedGoogle Scholar
  359. Xiao J, Yang B, Lin H, Lu Y, Luo X, Wang Z (2007) Novel approaches for gene-specific interference via manipulating actions of microRNAs: examination on the pacemaker channel genes HCN2 and HCN4. J Cell Physiol 212:285–292PubMedGoogle Scholar
  360. Yelin R, Dahary D, Sorek R, Levanon EY, Goldstein O, Shoshan A, Diber A, Biton S, Tamir Y, Khosravi R et al (2003) Widespread occurrence of antisense transcription in the human genome. Nat Biotechnol 21:379–386PubMedGoogle Scholar
  361. Yin H, Betts C, Saleh AF, Ivanova GD, Lee H, Seow Y, Kim D, Gait MJ, Wood MJ (2010) Optimization of peptide nucleic acid antisense oligonucleotides for local and systemic dystrophin splice correction in the mdx mouse. Mol Ther: J Am Soc Gene Ther 18:819–827Google Scholar
  362. Yokota T, Lu QL, Partridge T, Kobayashi M, Nakamura A, Takeda S, Hoffman E (2009) Efficacy of systemic morpholino exon-skipping in Duchenne dystrophy dogs. Ann Neurol 65:667–676PubMedGoogle Scholar
  363. Yong J, Wan L, Dreyfuss G (2004) Why do cells need an assembly machine for RNA-protein complexes? Trends Cell Biol 14:226–232PubMedGoogle Scholar
  364. Younger ST, Corey DR (2011) Transcriptional gene silencing in mammalian cells by miRNA mimics that target gene promoters. Nucleic Acids Res 39(13):5682–5691PubMedCentralPubMedGoogle Scholar
  365. Yu D, Pendergraff H, Liu J, Kordasiewicz HB, Cleveland DW, Swayze EE, Lima WF, Crooke ST, Prakash TP, Corey DR (2012) Single-stranded RNAs use RNAi to potently and allele-selectively inhibit mutant huntingtin expression. Cell 150:895–908PubMedCentralPubMedGoogle Scholar
  366. Yu RZ, Zhang H, Geary RS, Graham M, Masarjian L, Lemonidis K, Crooke R, Dean NM, Levin AA (2001) Pharmacokinetics and pharmacodynamics of an antisense phosphorothioate oligonucleotide targeting Fas mRNA in mice. J Pharmacol Exp Ther 296:388–395PubMedGoogle Scholar
  367. Zamecnik PC, Stephenson ML (1978) Inhibition of Rous sarcoma virus replication and cell transformation by a specific oligodeoxynucleotide. Proc Natl Acad Sci U S A 75:280–284PubMedCentralPubMedGoogle Scholar
  368. Zammarchi F, de Stanchina E, Bournazou E, Supakorndej T, Martires K, Riedel E, Corben AD, Bromberg JF, Cartegni L (2011) Antitumorigenic potential of STAT3 alternative splicing modulation. Proc Natl Acad Sci U S A 108(43):17779–17784PubMedCentralPubMedGoogle Scholar
  369. Zhao J, Ohsumi TK, Kung JT, Ogawa Y, Grau DJ, Sarma K, Song JJ, Kingston RE, Borowsky M, Lee JT (2010) Genome-wide identification of polycomb-associated RNAs by RIP-seq. Mol Cell 40:939–953PubMedCentralPubMedGoogle Scholar
  370. Zhou H, Janghra N, Mitrpant C, Dickinson RL, Anthony K, Price L, Eperon IC, Wilton SD, Morgan J, Muntoni F (2013) A novel morpholino oligomer targeting ISS-N1 improves rescue of severe spinal muscular atrophy transgenic mice. Hum Gene Ther 24:331–342PubMedCentralPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Isis PharmaceuticalsCarlsbadUSA

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