How the discovery of ISS-N1 led to the first medical therapy for spinal muscular atrophy

Abstract

Spinal muscular atrophy (SMA), a prominent genetic disease of infant mortality, is caused by low levels of survival motor neuron (SMN) protein owing to deletions or mutations of the SMN1 gene. SMN2, a nearly identical copy of SMN1 present in humans, cannot compensate for the loss of SMN1 because of predominant skipping of exon 7 during pre-mRNA splicing. With the recent US Food and Drug Administration approval of nusinersen (Spinraza), the potential for correction of SMN2 exon 7 splicing as an SMA therapy has been affirmed. Nusinersen is an antisense oligonucleotide that targets intronic splicing silencer N1 (ISS-N1) discovered in 2004 at the University of Massachusetts Medical School. ISS-N1 has emerged as the model target for testing the therapeutic efficacy of antisense oligonucleotides using different chemistries as well as different mouse models of SMA. Here, we provide a historical account of events that led to the discovery of ISS-N1 and describe the impact of independent validations that raised the profile of ISS-N1 as one of the most potent antisense targets for the treatment of a genetic disease. Recent approval of nusinersen provides a much-needed boost for antisense technology that is just beginning to realize its potential. Beyond treating SMA, the ISS-N1 target offers myriad potentials for perfecting various aspects of the nucleic-acid-based technology for the amelioration of the countless number of pathological conditions.

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References

  1. 1

    Awano T, Kim J-K, Monani UR . Spinal muscular atrophy: journeying from bench to bedside. Neurotherapeutics 2014; 11: 786–795.

    Article  PubMed  PubMed Central  Google Scholar 

  2. 2

    Sugarman EA, Nagan N, Zhu H, Akmaev VR, Zhou Z, Rohlfs EM et al. Pan-ethnic carrier screening and prenatal diagnosis for spinal muscular atrophy: clinical laboratory analysis of >72,400 specimens. Eur J Hum Genet 2012; 20: 27–32.

    Article  Google Scholar 

  3. 3

    Lefebvre S, Bürglen L, Reboullet S, Clermont O, Burlet P, Viollet L et al. Identification and characterization of a spinal muscular atrophy-determining gene. Cell 1995; 80: 155–165.

    CAS  Article  Google Scholar 

  4. 4

    Wirth B . An update of the mutation spectrum of the survival motor neuron gene (SMN1) in autosomal recessive spinal muscular atrophy (SMA). Hum Mutat 2000; 15: 228–237.

    CAS  Article  Google Scholar 

  5. 5

    Singh RN, Howell MD, Ottesen EW, Singh NN . Diverse role of survival motor neuron protein. Biochim Biophys Acta 2017; 1860: 299–315.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. 6

    Ahmad S, Bhatia K, Kannan A, Gangwani L . Molecular mechanisms of neurodegeneration in spinal muscular atrophy. J Exp Neurosci 2016; 10: 39–49.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. 7

    Shababi M, Habibi J, Yang HT, Vale SM, Sewell WA, Lorson CL . Cardiac defects contribute to the pathology of spinal muscular atrophy models. Hum Mol Genet 2010; 19: 4059–4071.

    CAS  Article  PubMed  Google Scholar 

  8. 8

    Heier CR, Satta R, Lutz C, DiDonato CJ . Arrhythmia and cardiac defects are a feature of spinal muscular atrophy model mice. Hum Mol Genet 2010; 19: 3906–3918.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. 9

    Schreml J, Riessland M, Paterno M, Garbes L, Roßbach K, Ackermann B et al. Severe SMA mice show organ impairment that cannot be rescued by therapy with the HDACi JNJ-26481585. Eur J Hum Genet 2013; 21: 643–652.

    CAS  Article  PubMed  Google Scholar 

  10. 10

    Michaud M, Arnoux T, Bielli S, Durand E, Rotrou Y, Jablonka S et al. Neuromuscular defects and breathing disorders in a new mouse model of spinal muscular atrophy. Neurobiol Dis 2010; 38: 125–135.

    Article  PubMed  Google Scholar 

  11. 11

    Shanmugarajan S, Tsuruga E, Swoboda KJ, Maria BL, Ries WL, Reddy SV . Bone loss in survival motor neuron (Smn(−/−) SMN2) genetic mouse model of spinal muscular atrophy. J Pathol 2009; 219: 52–60.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. 12

    Gombash SE, Cowley CJ, Fitzgerald JA, Iyer CC, Fried D, McGovern VL et al. SMN deficiency disrupts gastrointestinal and enteric nervous system function in mice. Hum Mol Genet 2015; 24: 3847–3860.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. 13

    Sintusek P, Catapano F, Angkathunkayul N, Marrosu E, Parson SH, Morgan JE et al. Histopathological defects in intestine in severe spinal muscular atrophy mice are improved by systemic antisense oligonucleotide treatment. PLoS One 2016; 11: e0155032.

    Article  PubMed  PubMed Central  Google Scholar 

  14. 14

    Vitte JM, Davoult B, Roblot N, Mayer M, Joshi V, Courageot S et al. Deletion of murine Smn exon 7 directed to liver leads to severe defect of liver development associated with iron overload. Am J Pathol 2004; 165: 1731–1741.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. 15

    Szunyogova E, Zhou H, Maxwell GK, Powis RA, Francesco M, Gillingwater TH et al. Survival motor neuron (SMN) protein is required for normal mouse liver development. Sci Rep 2016; 6: 34635.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. 16

    Bowerman M, Swoboda KJ, Michalski J-P, Wang G-S, Reeks C, Beauvais A et al. Glucose metabolism and pancreatic defects in spinal muscular atrophy. Ann Neurol 2012; 72: 256–268.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. 17

    Thomson AK, Somers E, Powis RA, Shorrock HK, Murphy K, Swoboda KJ et al. Survival of motor neurone protein is required for normal postnatal development of the spleen. J Anat 2016; 230: 337–346.

    Article  PubMed  PubMed Central  Google Scholar 

  18. 18

    Ottesen EW, Howell MD, Singh NN, Seo J, Whitley EM, Singh RN . Severe impairment of male reproductive organ development in a low SMN expressing mouse model of spinal muscular atrophy. Sci Rep 2016; 6: 20193.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. 19

    Lorson CL, Hahnen E, Androphy EJ, Wirth B . A single nucleotide in the SMN gene regulates splicing and is responsible for spinal muscular atrophy. Proc Natl Acad Sci USA 1999; 96: 6307–6311.

    CAS  Article  PubMed  Google Scholar 

  20. 20

    Monani UR, Lorson CL, Parsons DW, Prior TW, Androphy EJ, Burghes AH et al. A single nucleotide difference that alters splicing patterns distinguishes the SMA gene SMN1 from the copy gene SMN2. Hum Mol Genet 1999; 8: 1177–1183.

    CAS  Article  Google Scholar 

  21. 21

    Seo J, Howell MD, Singh NN, Singh RN . Spinal muscular atrophy: an update on therapeutic progress. Biochim Biophys Acta 2013; 1832: 2180–2190.

    CAS  Article  PubMed  Google Scholar 

  22. 22

    Howell MD, Singh NN, Singh RN . Advances in therapeutic development for spinal muscular atrophy. Future Med Chem 2014; 6: 1081–1099.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. 23

    Lorson CL, Androphy EJ . An exonic enhancer is required for inclusion of an essential exon in the SMA-determining gene SMN. Hum Mol Genet 2000; 9: 259–265.

    CAS  Article  PubMed  Google Scholar 

  24. 24

    Vitte J, Fassier C, Tiziano FD, Dalard C, Soave S, Roblot N et al. Refined characterization of the expression and stability of the SMN gene products. Am J Pathol 2007; 171: 1269–1280.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. 25

    Burnett BG, Muñoz E, Tandon A, Kwon DY, Sumner CJ, Fischbeck KH . Regulation of SMN protein stability. Mol Cell Biol 2009; 29: 1107–1115.

    CAS  Article  PubMed  Google Scholar 

  26. 26

    Cho S, Dreyfuss G . A degron created by SMN2 exon 7 skipping is a principal contributor to spinal muscular atrophy severity. Genes Dev 2010; 24: 438–442.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. 27

    Lee Y, Rio DC . Mechanisms and regulation of alternative pre-mRNA splicing. Annu Rev Biochem 2015; 84: 291–323.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. 28

    Singh NN, Singh RN . Alternative splicing in spinal muscular atrophy underscores the role of an intron definition model. RNA Biol 2011; 8: 600–606.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. 29

    Singh NN, Lee BM, Singh RN . Splicing regulation in spinal muscular atrophy by an RNA structure formed by long-distance interactions. Ann NY Acad Sci 2015; 1341: 176–187.

    CAS  Article  PubMed  Google Scholar 

  30. 30

    Singh NN, Howell MD, Singh RN. Transcriptional and splicing regulation of spinal muscular atrophy genes. In: Sumner CJ, Paushkin S, Ko C-P (eds). Spinal Muscular Atrophy. Academic Press: New York, USA, 2017; pp 75–97.

    Google Scholar 

  31. 31

    Setola V, Terao M, Locatelli D, Bassanini S, Garattini E, Battaglia G . Axonal-SMN (a-SMN), a protein isoform of the survival motor neuron gene, is specifically involved in axonogenesis. Proc Natl Acad Sci USA 2007; 104: 1959–1964.

    CAS  Article  PubMed  Google Scholar 

  32. 32

    Singh NN, Seo J, Rahn SJ, Singh RN . A multi-exon-skipping detection assay reveals surprising diversity of splice isoforms of spinal muscular atrophy genes. PLoS One 2012; 7: e49595.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. 33

    Seo J, Singh NN, Ottesen EW, Sivanesan S, Shishimorova M, Singh RN . Oxidative stress triggers body-wide skipping of multiple exons of the spinal muscular atrophy gene. PLoS One 2016; 11: e0154390.

    Article  PubMed  PubMed Central  Google Scholar 

  34. 34

    Seo J, Singh NN, Ottesen EW, Lee BM, Singh RN . A novel human-specific splice isoform alters the critical C-terminus of survival motor neuron protein. Sci Rep 2016; 6: 30778.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  35. 35

    Ottesen EW . ISS-N1 makes the first FDA-approved drug for spinal muscular atrophy. Translat Neurosci 2017; 8: 1–6.

    CAS  Article  Google Scholar 

  36. 36

    Singh NN, Androphy EJ, Singh RN . An extended inhibitory context causes skipping of exon 7 of SMN2 in spinal muscular atrophy. Biochem Biophys Res Commun 2004; 315: 381–388.

    CAS  Article  PubMed  Google Scholar 

  37. 37

    Singh NN, Androphy EJ, Singh RN . The regulation and regulatory activities of alternative splicing of the SMN gene. Crit Rev Eukaryot Gene Expr 2004; 14: 271–285.

    CAS  Article  PubMed  Google Scholar 

  38. 38

    Singh RN . Evolving concepts on human SMN pre-mRNA splicing. RNA Biol 2007; 4: 7–10.

    CAS  Article  PubMed  Google Scholar 

  39. 39

    Singh NN, Androphy EJ, Singh RN . In vivo selection reveals combinatorial controls that define a critical exon in the spinal muscular atrophy genes. RNA 2004; 10: 1291–1305.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  40. 40

    Singh RN . Unfolding the mystery of alternative splicing through a unique method of in vivo selection. Front Biosci 2007; 12: 3263–3272.

    CAS  Article  PubMed  Google Scholar 

  41. 41

    Singh RN, Singh NN. . Functional analysis of large exonic sequences through iterative in vivo selection In: Stamm S, Smith CWJ, Lührmann R (eds). Alternative Pre-mRNA Splicing: Theory and Protocols. Wiley: Weinheim, Germany, 2012; pp 200–209.

    Google Scholar 

  42. 42

    Singh NN, Singh RN, Androphy EJ . Modulating role of RNA structure in alternative splicing of a critical exon in the spinal muscular atrophy genes. Nucleic Acids Res 2007; 35: 371–389.

    CAS  Article  PubMed  Google Scholar 

  43. 43

    Singh NK, Singh NN, Androphy EJ, Singh RN . 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 2006; 26: 1333–1346.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  44. 44

    Singh RN, Singh NN, Singh NK, Androphy EJ . Spinal muscular atrophy (SMA) treatment via targeting of SMN2 splice site inhibitory sequences. US patent publication no. US7838657 (also published as US8110560, US8586559, US9476042, US20070292408, US20100087511, US20120165394, US20140066492), 2010.

  45. 45

    Buratti E, Baralle M, Baralle FE . Defective splicing, disease and therapy: searching for master checkpoints in exon definition. Nucleic Acids Res 2006; 34: 3494–3510.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  46. 46

    Hua Y, Vickers TA, Baker BF, Bennett CF, Krainer AR . Enhancement of SMN2 exon 7 inclusion by antisense oligonucleotides targeting the exon. PLoS Biol 2007; 5: e73.

    Article  PubMed  PubMed Central  Google Scholar 

  47. 47

    Hua Y, Vickers TA, Okunola HL, Bennett CF, Krainer AR . Antisense masking of an hnRNP A1/A2 intronic splicing silencer corrects SMN2 splicing in transgenic mice. Am J Hum Genet 2008; 82: 834–848.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  48. 48

    Hua Y, Sahashi K, Hung G, Rigo F, Passini MA, Bennett CF et al. Antisense correction of SMN2 splicing in the CNS rescues necrosis in a type III SMA mouse model. Genes Dev 2010; 24: 1634–1644.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  49. 49

    Passini MA, Bu J, Richards AM, Kinnecom C, Sardi SP, Stanek LM et al. Antisense oligonucleotides delivered to the mouse CNS ameliorate symptoms of severe spinal muscular atrophy. Sci Transl Med 2011; 3: 72ra18.

    Article  PubMed  PubMed Central  Google Scholar 

  50. 50

    Hua Y, Sahashi K, Rigo F, Hung G, Horev G, Bennett CF et al. Peripheral SMN restoration is essential for long-term rescue of a severe spinal muscular atrophy mouse model. Nature 2011; 478: 123–126.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  51. 51

    Porensky PN, Mitrpant C, McGovern VL, Bevan AK, Foust KD, Kaspar BK et al. A single administration of morpholino antisense oligomer rescues spinal muscular atrophy in mouse. Hum Mol Genet 2012; 21: 1625–1638.

    CAS  Article  Google Scholar 

  52. 52

    Zhou H, Janghra N, Mitrpant C, Dickinson RL, Anthony K, Price L et al. A novel morpholino oligomer targeting ISS-N1 improves rescue of severe spinal muscular atrophy transgenic mice. Hum Gene Ther 2013; 24: 331–342.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  53. 53

    Mitrpant C, Porensky P, Zhou H, Price L, Muntoni F, Fletcher S et al. Improved antisense oligonucleotide design to suppress aberrant SMN2 gene transcript processing: towards a treatment for spinal muscular atrophy. PLOS One 2013; 8: e62114.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  54. 54

    Zhou H, Meng J, Marrosu E, Janghra N, Morgan J, Muntoni F . Repeated low doses of morpholino antisense oligomer: an intermediate mouse model of spinal muscular atrophy to explore the window of therapeutic response. Hum Mol Genet 2015; 24: 6265–6277.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  55. 55

    Singh NN, Seo J, Ottesen EW, Shishimorova M, Bhattacharya D, Singh RN . TIA1 prevents skipping of a critical exon associated with spinal muscular atrophy. Mol Cell Biol 2011; 31: 935–954.

    CAS  Article  PubMed  Google Scholar 

  56. 56

    Singh NN, Shishimorova M, Cao LC, Gangwani L, Singh RN . A short antisense oligonucleotide masking a unique intronic motif prevents skipping of a critical exon in spinal muscular atrophy. RNA Biol 2009; 6: 341–350.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  57. 57

    Singh NN, Hollinger K, Bhattacharya D, Singh RN . An antisense microwalk reveals critical role of an intronic position linked to a unique long-distance interaction in pre-mRNA splicing. RNA 2010; 16: 1167–1181.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  58. 58

    Singh NN, Lawler MN, Ottesen EW, Upreti D, Kaczynski JR, Singh RN . An intronic structure enabled by a long-distance interaction serves as a novel target for splicing correction in spinal muscular atrophy. Nucleic Acids Res 2013; 41: 8144–8165.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  59. 59

    Singh NN, Lee BM, DiDonato CJ, Singh RN . Mechanistic principles of antisense targets for the treatment of spinal muscular atrophy. Future Med Chem 2015; 7: 1793–1808.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  60. 60

    Rogalska ME, Tajnik M, Licastro D, Bussani E, Camparini L, Mattioli C et al. Therapeutic activity of modified U1 core spliceosomal particles. Nat Commun 2016; 7: 11168.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  61. 61

    Williams JH, Schray RC, Patterson CA, Ayitey SO, Tallent MK, Lutz GJ . Oligonucleotide-mediated survival of motor neuron protein expression in CNS improves phenotype in a mouse model of spinal muscular atrophy. J Neurosci 2009; 29: 7633–7638.

    CAS  Article  PubMed  Google Scholar 

  62. 62

    Osman EY, Yen P-F, Lorson CL . 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 2012; 20: 119–126.

    CAS  Article  PubMed  Google Scholar 

  63. 63

    Arnold WD, Porensky PN, McGovern VL, Iyer CC, Duque S, Li X et al. Electrophysiological biomarkers in spinal muscular atrophy: preclinical proof of concept. Ann Clin Transl Neurol 2014; 1: 34–44.

    Article  PubMed  Google Scholar 

  64. 64

    Nizzardo M, Simone C, Salani S, Ruepp M-D, Rizzo F, Ruggieri M et al. Effect of combined systemic and local morpholino treatment on the spinal muscular atrophy Δ7 mouse model phenotype. Clin Ther 2014; 36: 340–356.e5.

    CAS  Article  PubMed  Google Scholar 

  65. 65

    Arnold W, McGovern VL, Sanchez B, Li J, Corlett KM, Kolb SJ et al. The neuromuscular impact of symptomatic SMN restoration in a mouse model of spinal muscular atrophy. Neurobiol Dis 2016; 87: 116–123.

    CAS  Article  PubMed  Google Scholar 

  66. 66

    Arnold WD, Duque S, Iyer CC, Zaworski P, McGovern VL, Taylor SJ et al. Normalization of patient-identified plasma biomarkers in SMNΔ7 mice following postnatal SMN restoration. PLoS One 2016; 11: e0167077.

    Article  PubMed  PubMed Central  Google Scholar 

  67. 67

    Hua Y, Liu YH, Sahashi K, Rigo F, Bennett CF, Krainer AR . Motor neuron cell-nonautonomous rescue of spinal muscular atrophy phenotypes in mild and severe transgenic mouse models. Genes Dev 2015; 29: 288–297.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  68. 68

    Lin T-L, Chen T-H, Hsu Y-Y, Cheng Y-H, Juang B-T, Jong Y-J . Selective neuromuscular denervation in Taiwanese severe SMA mouse can be reversed by morpholino antisense oligonucleotides. PLoS One 2016; 11: e0154723.

    Article  PubMed  PubMed Central  Google Scholar 

  69. 69

    Catapano F, Zaharieva I, Scoto M, Marrosu E, Morgan J, Muntoni F et al. Altered levels of microRNA-9, -206, and -132 in spinal muscular atrophy and their response to antisense oligonucleotide therapy. Mol Ther Nucleic Acids 2016; 5: e331.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  70. 70

    Hammond SM, Hazell G, Shabanpoor F, Saleh AF, Bowerman M, Sleigh JN et al. Systemic peptide-mediated oligonucleotide therapy improves long-term survival in spinal muscular atrophy. Proc Natl Acad Sci USA 2016; 113: 10962–10967.

    CAS  Article  Google Scholar 

  71. 71

    Shabanpoor F, Hammond SM, Abendroth F, Hazell G, Wood MJA, Gait MJ . Identification of a peptide for systemic brain delivery of a morpholino oligonucleotide in mouse models of spinal muscular atrophy. Nucleic Acid Ther 2017 doi:10.1089/nat.2016.0652.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  72. 72

    Bogdanik LP, Osborne MA, Davis C, Martin WP, Austin A, Rigo F et al. Systemic, postsymptomatic antisense oligonucleotide rescues motor unit maturation delay in a new mouse model for type II/III spinal muscular atrophy. Proc Natl Acad Sci USA 2015; 112: E5863–E5872.

    CAS  Article  PubMed  Google Scholar 

  73. 73

    Hosseinibarkooie S, Peters M, Torres-Benito L, Rastetter RH, Hupperich K, Hoffmann A et al. The power of human protective modifiers: PLS3 and CORO1C unravel impaired endocytosis in spinal muscular atrophy and rescue SMA phenotype. Am J Hum Genet 2016; 99: 647–665.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  74. 74

    Chiriboga CA, Swoboda KJ, Darras BT, Iannaccone ST, Montes J, De Vivo DC et al. Results from a phase 1 study of nusinersen (ISIS-SMN(Rx)) in children with spinal muscular atrophy. Neurology 2016; 86: 890–897.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  75. 75

    Haché M, Swoboda KJ, Sethna N, Farrow-Gillespie A, Khandji A, Xia S et al. Intrathecal injections in children with spinal muscular atrophy: nusinersen clinical trial experience. J Child Neurol 2016; 31: 899–906.

    Article  PubMed  PubMed Central  Google Scholar 

  76. 76

    Finkel RS, Chiriboga CA, Vajsar J, Day JW, Montes J, De Vivo DC et al. Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study. Lancet 2016; 388: 3017–3026.

    CAS  Article  Google Scholar 

  77. 77

    Garber K . Big win possible for Ionis/Biogen antisense drug in muscular atrophy. Nat Biotechnol 2016; 34: 1002–1003.

    CAS  Article  PubMed  Google Scholar 

  78. 78

    Osman EY, Miller MR, Robbins KL, Lombardi AM, Atkinson AK, Brehm AJ et al. Morpholino antisense oligonucleotides targeting intronic repressor Element1 improve phenotype in SMA mouse models. Hum Mol Genet 2014; 23: 4832–4845.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  79. 79

    Howell MD, Ottesen EW, Singh NN, Anderson RL, Singh RN . Gender-specific amelioration of SMA phenotype upon disruption of a deep intronic structure by an oligonucleotide. Mol Ther 2017 doi:10.1016/j.ymthe.2017.03.036.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  80. 80

    Pao PW, Wee KB, Yee WC, Pramono ZAD, Dwipramono ZA . Dual masking of specific negative splicing regulatory elements resulted in maximal exon 7 inclusion of SMN2 gene. Mol Ther 2014; 22: 854–861.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The nonprofit organization Cure SMA (formerly Families of SMA) supported the initial studies in the laboratories of Drs Ravindra Singh and Elliot Androphy, which led to the discovery of the ISS-N1 target at the University Massachusetts Medical School. RNS is supported by US National Institutes of Health NIH R01 NS055925, Iowa Center of Advanced Neurotoxicology (ICAN) and Salsbury Endowment at Iowa State University. EJA is grateful for support from NIH Grants R01 NS040275 and R01 NS0682284 and Cure SMA.

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Correspondence to R N Singh.

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Competing interests

The ISS-N1 target (US7838657) was discovered in the Singh laboratory at UMass Medical School (MA, USA). Inventors, including RNS, NNS, EJA and UMASS Medical School, are currently benefiting from licensing of the ISS-N1 target to Ionis Pharmaceuticals. Iowa State University holds intellectual property rights on GC-rich sequence (GCRS) and ISS-N2 targets. Therefore, inventors including RNS, NNS and Iowa State University could potentially benefit from any future commercial exploitation of GCRS and ISS-N2 targets. MDH has no conflict of interest to declare.

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Singh, N., Howell, M., Androphy, E. et al. How the discovery of ISS-N1 led to the first medical therapy for spinal muscular atrophy. Gene Ther 24, 520–526 (2017). https://doi.org/10.1038/gt.2017.34

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