Skip to main content
SpringerLink
Log in

An Overview of Recent Advances and Clinical Applications of Exon Skipping and Splice Modulation for Muscular Dystrophy and Various Genetic Diseases

  • Protocol
  • First Online:
Exon Skipping and Inclusion Therapies

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1828))

Abstract

Exon skipping is a therapeutic approach that is feasible for various genetic diseases and has been studied and developed for over two decades. This approach uses antisense oligonucleotides (AON) to modify the splicing of pre-mRNA to correct the mutation responsible for a disease, or to suppress a particular gene expression, as in allergic diseases. Antisense-mediated exon skipping is most extensively studied in Duchenne muscular dystrophy (DMD) and has developed from in vitro proof-of-concept studies to clinical trials targeting various single exons such as exon 45 (casimersen), exon 53 (NS-065/NCNP-01, golodirsen), and exon 51 (eteplirsen). Eteplirsen (brand name Exondys 51), is the first approved antisense therapy for DMD in the USA, and provides a treatment option for ~14% of all DMD patients, who are amenable to exon 51 skipping. Eteplirsen is granted accelerated approval and marketing authorization by the US Food and Drug Administration (FDA), on the condition that additional postapproval trials show clinical benefit. Permanent exon skipping achieved at the DNA level using clustered regularly interspaced short palindromic repeats (CRISPR) technology holds promise in current preclinical trials for DMD. In hopes of achieving clinical success parallel to DMD, exon skipping and splice modulation are also being studied in other muscular dystrophies, such as Fukuyama congenital muscular dystrophy (FCMD), dysferlinopathy including limb-girdle muscular dystrophy type 2B (LGMD2B), Miyoshi myopathy (MM), and distal anterior compartment myopathy (DMAT), myotonic dystrophy, and merosin-deficient congenital muscular dystrophy type 1A (MDC1A). This chapter also summarizes the development of antisense-mediated exon skipping therapy in diseases such as Usher syndrome, dystrophic epidermolysis bullosa, fibrodysplasia ossificans progressiva (FOP), and allergic diseases.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 139.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 179.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 249.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Zhang L, Li X, Zhao R (2013) Structural analyses of the pre-mRNA splicing machinery. Protein Sci 22(6):677–692. https://doi.org/10.1002/pro.2266

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Veltrop M, Aartsma-Rus A (2014) Antisense-mediated exon skipping: taking advantage of a trick from mother nature to treat rare genetic diseases. Exp Cell Res 325(1):50–55. https://doi.org/10.1016/j.yexcr.2014.01.026

    Article  CAS  PubMed  Google Scholar 

  3. Sardone V, Zhou H, Muntoni F et al (2017) Antisense oligonucleotide-based therapy for neuromuscular disease. Molecules 22(4):E563. https://doi.org/10.3390/molecules22040563

    Article  PubMed  Google Scholar 

  4. Stein CA, Castanotto D (2017) FDA-approved oligonucleotide therapies in 2017. Mol Ther 25(5):1069–1075. https://doi.org/10.1016/j.ymthe.2017.03.023

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Nowak KJ, Davies KE (2004) Duchenne muscular dystrophy and dystrophin: pathogenesis and opportunities for treatment. EMBO Rep 5(9):872–876. https://doi.org/10.1038/sj.embor.7400221

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Hoffman EP, Brown RH, Kunkel LM (1992) Dystrophin: the protein product of the Duchene muscular dystrophy locus. 1987. Biotechnology 24:457–466

    CAS  PubMed  Google Scholar 

  7. Nichols B, Takeda S, Yokota T (2015) Nonmechanical roles of dystrophin and associated proteins in exercise, neuromuscular junctions, and brains. Brain Sci 5(3):275–298. https://doi.org/10.3390/brainsci5030275

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Aoki Y, Nakamura A, Yokota T et al (2010) In-frame dystrophin following exon 51-skipping improves muscle pathology and function in the exon 52-deficient mdx mouse. Mol Ther 18(11):1995–2005. https://doi.org/10.1038/mt.2010.186

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Wein N, Vulin A, Findlay AR et al (2017) Efficient skipping of single exon duplications in DMD patient-derived cell lines using an antisense oligonucleotide approach. J Neuromuscul Dis 4(3):199–207. https://doi.org/10.3233/JND-170233

    Article  PubMed  Google Scholar 

  10. Maruyama R, Echigoya Y, Caluseriu O et al (2017) Systemic delivery of morpholinos to skip multiple exons in a dog model of duchenne muscular dystrophy. Methods Mol Biol 1565:201–213. https://doi.org/10.1007/978-1-4939-6817-6_17

    Article  CAS  PubMed  Google Scholar 

  11. Yokota T, Duddy W, Echigoya Y et al (2012) Exon skipping for nonsense mutations in Duchenne muscular dystrophy: too many mutations, too few patients? Expert Opin Biol Ther 12(9):1141–1152. https://doi.org/10.1517/14712598.2012.693469

    Article  CAS  PubMed  Google Scholar 

  12. Lu QL, Rabinowitz A, Chen YC et al (2005) Systemic delivery of antisense oligoribonucleotide restores dystrophin expression in body-wide skeletal muscles. Proc Natl Acad Sci U S A 102(1):198–203. https://doi.org/10.1073/pnas.0406700102

    Article  CAS  PubMed  Google Scholar 

  13. Monaco AP, Bertelson CJ, Liechti-Gallati S et al (1988) An explanation for the phenotypic differences between patients bearing partial deletions of the DMD locus. Genomics 2(1):90–95

    Article  CAS  PubMed  Google Scholar 

  14. Aartsma-Rus A, Van Deutekom JC, Fokkema IF et al (2006) Entries in the Leiden Duchenne muscular dystrophy mutation database: an overview of mutation types and paradoxical cases that confirm the reading-frame rule. Muscle Nerve 34(2):135–144. https://doi.org/10.1002/mus.20586

    Article  CAS  PubMed  Google Scholar 

  15. Bladen CL, Salgado D, Monges S et al (2015) The TREAT-NMD DMD global database: analysis of more than 7,000 Duchenne muscular dystrophy mutations. Hum Mutat 36(4):395–402. https://doi.org/10.1002/humu.22758

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Aartsma-Rus A, Fokkema I, Verschuuren J et al (2009) Theoretic applicability of antisense-mediated exon skipping for Duchenne muscular dystrophy mutations. Hum Mutat 30(3):293–299. https://doi.org/10.1002/humu.20918

    Article  PubMed  Google Scholar 

  17. Release FN (2016) FDA grants accelerated approval to first drug for Duchenne muscular dystrophy. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm521263.htm

  18. Aartsma-Rus A, Krieg AM (2017) FDA approves eteplirsen for duchenne muscular dystrophy: the next chapter in the eteplirsen saga. Nucleic Acid Ther 27(1):1–3. https://doi.org/10.1089/nat.2016.0657

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Mitrpant C, Fletcher S, Iversen PL et al (2009) By-passing the nonsense mutation in the 4 CV mouse model of muscular dystrophy by induced exon skipping. J Gene Med 11(1):46–56. https://doi.org/10.1002/jgm.1265

    Article  CAS  PubMed  Google Scholar 

  20. Yokota T, Lu QL, Partridge T et al (2009) Efficacy of systemic morpholino exon-skipping in Duchenne dystrophy dogs. Ann Neurol 65(6):667–676. https://doi.org/10.1002/ana.21627

    Article  PubMed  PubMed Central  Google Scholar 

  21. Niks EH, Aartsma-Rus A (2017) Exon skipping: a first in class strategy for Duchenne muscular dystrophy. Expert Opin Biol Ther 17(2):225–236. https://doi.org/10.1080/14712598.2017.1271872

    Article  CAS  PubMed  Google Scholar 

  22. Shimo T, Maruyama R, Yokota T (2018) Designing effective antisense oligonucleotides for exon skipping. Methods Mol Biol 1687:143–155. https://doi.org/10.1007/978-1-4939-7374-3_10

    Article  CAS  PubMed  Google Scholar 

  23. Maruyama R, Echigoya Y, Nakamura A et al. (2017) Systemic injections of peptide-conjugated morpholinos improve cardiac symptoms of a dog model of duchenne muscular dystrophy. Paper presented at the MOLECULAR THERAPY,

    Google Scholar 

  24. Aartsma-Rus A, Janson AA, Kaman WE et al (2004) Antisense-induced multiexon skipping for Duchenne muscular dystrophy makes more sense. Am J Hum Genet 74(1):83–92. https://doi.org/10.1086/381039

    Article  CAS  PubMed  Google Scholar 

  25. Beroud C, Tuffery-Giraud S, Matsuo M et al (2007) Multiexon skipping leading to an artificial DMD protein lacking amino acids from exons 45 through 55 could rescue up to 63% of patients with Duchenne muscular dystrophy. Hum Mutat 28(2):196–202. https://doi.org/10.1002/humu.20428

    Article  CAS  PubMed  Google Scholar 

  26. van Vliet L, de Winter CL, van Deutekom JC et al (2008) Assessment of the feasibility of exon 45-55 multiexon skipping for Duchenne muscular dystrophy. BMC Med Genet 9:105. https://doi.org/10.1186/1471-2350-9-105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Echigoya Y, Aoki Y, Miskew B et al (2015) Long-term efficacy of systemic multiexon skipping targeting dystrophin exons 45-55 with a cocktail of vivo-morpholinos in mdx52 mice. Mol Ther Nucleic Acids 4:e225. https://doi.org/10.1038/mtna.2014.76

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Echigoya Y, Nakamura A, Nagata T et al (2017) Effects of systemic multiexon skipping with peptide-conjugated morpholinos in the heart of a dog model of Duchenne muscular dystrophy. Proc Natl Acad Sci U S A 114(16):4213–4218. https://doi.org/10.1073/pnas.1613203114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Nakamura A, Shiba N, Miyazaki D et al (2017) Comparison of the phenotypes of patients harboring in-frame deletions starting at exon 45 in the Duchenne muscular dystrophy gene indicates potential for the development of exon skipping therapy. J Hum Genet 62(4):459–463. https://doi.org/10.1038/jhg.2016.152

    Article  CAS  PubMed  Google Scholar 

  30. Yokota T, Takeda S, Lu QL et al (2009) A renaissance for antisense oligonucleotide drugs in neurology: exon skipping breaks new ground. Arch Neurol 66(1):32–38. https://doi.org/10.1001/archneurol.2008.540

    Article  PubMed  PubMed Central  Google Scholar 

  31. Aoki Y, Yokota T, Wood MJ (2013) Development of multiexon skipping antisense oligonucleotide therapy for Duchenne muscular dystrophy. Biomed Res Int 2013:402369. https://doi.org/10.1155/2013/402369

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Aoki Y, Yokota T, Nagata T et al (2012) Bodywide skipping of exons 45-55 in dystrophic mdx52 mice by systemic antisense delivery. Proc Natl Acad Sci U S A 109(34):13763–13768. https://doi.org/10.1073/pnas.1204638109

    Article  PubMed  PubMed Central  Google Scholar 

  33. Arechavala-Gomeza V, Graham IR, Popplewell LJ et al (2007) Comparative analysis of antisense oligonucleotide sequences for targeted skipping of exon 51 during dystrophin pre-mRNA splicing in human muscle. Hum Gene Ther 18(9):798–810. https://doi.org/10.1089/hum.2006.061

    Article  CAS  PubMed  Google Scholar 

  34. Mendell JR, Rodino-Klapac LR, Sahenk Z et al (2013) Eteplirsen for the treatment of Duchenne muscular dystrophy. Ann Neurol 74(5):637–647. https://doi.org/10.1002/ana.23982

    Article  CAS  PubMed  Google Scholar 

  35. Miyatake S, Mizobe Y, Takizawa H et al (2018) Exon skipping therapy using phosphorodiamidate morpholino oligomers in the mdx52 mouse model of duchenne muscular dystrophy. Methods Mol Biol 1687:123–141. https://doi.org/10.1007/978-1-4939-7374-3_9

    Article  CAS  PubMed  Google Scholar 

  36. Lim KR, Maruyama R, Yokota T (2017) Eteplirsen in the treatment of Duchenne muscular dystrophy. Drug Des Devel Ther 11:533–545. https://doi.org/10.2147/DDDT.S97635

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Mendell JR, Goemans N, Lowes LP et al (2016) Longitudinal effect of eteplirsen versus historical control on ambulation in Duchenne muscular dystrophy. Ann Neurol 79(2):257–271. https://doi.org/10.1002/ana.24555

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Nguyen Q, Yokota T (2017) Immortalized muscle cell model to test the exon skipping efficacy for duchenne muscular dystrophy. J Pers Med 7(4):13

    Article  PubMed Central  Google Scholar 

  39. Echigoya Y, Lim KRQ, Trieu N et al (2017) Quantitative antisense screening and optimization for exon 51 skipping in duchenne muscular dystrophy. Mol Ther 25(11):2561–2572. https://doi.org/10.1016/j.ymthe.2017.07.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Therapeutics S (2017) Sarepta therapeutics announces positive results in its study evaluating gene expression, dystrophin production, and dystrophin localization in patients with duchenne muscular dystrophy (DMD) amenable to skipping exon 53 treated with golodirsen (SRP-4053). http://investorrelations.sarepta.com/news-releases/news-release-details/sarepta-therapeutics-announces-positive-results-its-study. Accessed Sep 2017

  41. Mojica FJ, Diez-Villasenor C, Garcia-Martinez J et al (2005) Intervening sequences of regularly spaced prokaryotic repeats derive from foreign genetic elements. J Mol Evol 60(2):174–182. https://doi.org/10.1007/s00239-004-0046-3

    Article  CAS  PubMed  Google Scholar 

  42. Jansen R, Embden JD, Gaastra W et al (2002) Identification of genes that are associated with DNA repeats in prokaryotes. Mol Microbiol 43(6):1565–1575

    Article  CAS  PubMed  Google Scholar 

  43. Barrangou R, Fremaux C, Deveau H et al (2007) CRISPR provides acquired resistance against viruses in prokaryotes. Science 315(5819):1709–1712. https://doi.org/10.1126/science.1138140

    Article  CAS  PubMed  Google Scholar 

  44. Maeder ML, Gersbach CA (2016) Genome-editing technologies for gene and cell therapy. Mol Ther 24(3):430–446. https://doi.org/10.1038/mt.2016.10

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Gaj T, Gersbach CA, Barbas CF 3rd (2013) ZFN, TALEN, and CRISPR/Cas-based methods for genome engineering. Trends Biotechnol 31(7):397–405. https://doi.org/10.1016/j.tibtech.2013.04.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Li HL, Fujimoto N, Sasakawa N et al (2015) Precise correction of the dystrophin gene in duchenne muscular dystrophy patient induced pluripotent stem cells by TALEN and CRISPR-Cas9. Stem Cell Reports 4(1):143–154. https://doi.org/10.1016/j.stemcr.2014.10.013

    Article  CAS  PubMed  Google Scholar 

  47. Tabebordbar M, Zhu K, Cheng JKW et al (2016) In vivo gene editing in dystrophic mouse muscle and muscle stem cells. Science 351(6271):407–411. https://doi.org/10.1126/science.aad5177

    Article  CAS  PubMed  Google Scholar 

  48. Nelson CE, Hakim CH, Ousterout DG et al (2016) In vivo genome editing improves muscle function in a mouse model of Duchenne muscular dystrophy. Science 351(6271):403–407. https://doi.org/10.1126/science.aad5143

    Article  CAS  PubMed  Google Scholar 

  49. Long C, Amoasii L, Mireault AA et al (2016) Postnatal genome editing partially restores dystrophin expression in a mouse model of muscular dystrophy. Science 351(6271):400–403. https://doi.org/10.1126/science.aad5725

    Article  CAS  PubMed  Google Scholar 

  50. Ousterout DG, Kabadi AM, Thakore PI et al (2015) Multiplex CRISPR/Cas9-based genome editing for correction of dystrophin mutations that cause Duchenne muscular dystrophy. Nat Commun 6:6244. https://doi.org/10.1038/ncomms7244

    Article  CAS  PubMed  Google Scholar 

  51. Zetsche B, Gootenberg JS, Abudayyeh OO et al (2015) Cpf1 is a single RNA-guided endonuclease of a class 2 CRISPR-Cas system. Cell 163(3):759–771. https://doi.org/10.1016/j.cell.2015.09.038

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Shmakov S, Abudayyeh OO, Makarova KS et al (2015) Discovery and functional characterization of diverse class 2 CRISPR-Cas systems. Mol Cell 60(3):385–397. https://doi.org/10.1016/j.molcel.2015.10.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Zhang Y, Long C, Li H et al (2017) CRISPR-Cpf1 correction of muscular dystrophy mutations in human cardiomyocytes and mice. Sci Adv 3(4):e1602814. https://doi.org/10.1126/sciadv.1602814

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Kamoshita S, Konishi Y, Segawa M et al (1976) Congenital muscular dystrophy as a disease of the central nervous system. Arch Neurol 33(7):513–516

    Article  CAS  PubMed  Google Scholar 

  55. Toda T, Segawa M, Nomura Y et al (1993) Localization of a gene for Fukuyama type congenital muscular dystrophy to chromosome 9q31-33. Nat Genet 5(3):283–286. https://doi.org/10.1038/ng1193-283

    Article  CAS  PubMed  Google Scholar 

  56. Watanabe M, Kobayashi K, Jin F et al (2005) Founder SVA retrotransposal insertion in Fukuyama-type congenital muscular dystrophy and its origin in Japanese and northeast Asian populations. Am J Med Genet A 138(4):344–348. https://doi.org/10.1002/ajmg.a.30978

    Article  PubMed  Google Scholar 

  57. Kobayashi K, Nakahori Y, Miyake M et al (1998) An ancient retrotransposal insertion causes Fukuyama-type congenital muscular dystrophy. Nature 394(6691):388–392. https://doi.org/10.1038/28653

    Article  CAS  PubMed  Google Scholar 

  58. Hayashi YK, Ogawa M, Tagawa K et al (2001) Selective deficiency of alpha-dystroglycan in Fukuyama-type congenital muscular dystrophy. Neurology 57(1):115–121

    Article  CAS  PubMed  Google Scholar 

  59. Lee JJA, Yokota T (2016) Translational research in nucleic acid therapies for muscular dystrophies. In: Takeda SI, Miyagoe-Suzuki Y, Mori-Yoshimura M (eds) Translational research in muscular dystrophy. Springer, Japan, Tokyo, pp 87–102. https://doi.org/10.1007/978-4-431-55678-7_6

    Chapter  Google Scholar 

  60. Colombo R, Bignamini AA, Carobene A et al (2000) Age and origin of the FCMD 3′-untranslated-region retrotransposal insertion mutation causing Fukuyama-type congenital muscular dystrophy in the Japanese population. Hum Genet 107(6):559–567

    Article  CAS  PubMed  Google Scholar 

  61. Lee JJ, Yokota T (2013) Antisense therapy in neurology. J Pers Med 3(3):144–176. https://doi.org/10.3390/jpm3030144

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Taniguchi-Ikeda M, Kobayashi K, Kanagawa M et al (2011) Pathogenic exon-trapping by SVA retrotransposon and rescue in Fukuyama muscular dystrophy. Nature 478(7367):127–131. https://doi.org/10.1038/nature10456

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Harper PS (1975) Congenital myotonic dystrophy in Britain. II. Genetic basis. Arch Dis Child 50(7):514–521

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Klein AF, Dastidar S, Furling D et al (2015) Therapeutic approaches for dominant muscle diseases: highlight on myotonic dystrophy. Curr Gene Ther 15(4):329–337

    Article  CAS  PubMed  Google Scholar 

  65. Brook JD, McCurrach ME, Harley HG 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(4):799–808

    Article  CAS  PubMed  Google Scholar 

  66. Mahadevan M, Tsilfidis C, Sabourin L et al (1992) Myotonic dystrophy mutation: an unstable CTG repeat in the 3′ untranslated region of the gene. Science 255(5049):1253–1255

    Article  CAS  PubMed  Google Scholar 

  67. Fu YH, Pizzuti A, Fenwick RG Jr et al (1992) An unstable triplet repeat in a gene related to myotonic muscular dystrophy. Science 255(5049):1256–1258

    Article  CAS  PubMed  Google Scholar 

  68. Liquori CL, Ricker K, Moseley ML et al (2001) Myotonic dystrophy type 2 caused by a CCTG expansion in intron 1 of ZNF9. Science 293(5531):864–867. https://doi.org/10.1126/science.1062125

    Article  CAS  PubMed  Google Scholar 

  69. Klein AF, Gasnier E, Furling D (2011) Gain of RNA function in pathological cases: focus on myotonic dystrophy. Biochimie 93(11):2006–2012. https://doi.org/10.1016/j.biochi.2011.06.028

    Article  CAS  PubMed  Google Scholar 

  70. Charlet BN, Savkur RS, Singh G et al (2002) Loss of the muscle-specific chloride channel in type 1 myotonic dystrophy due to misregulated alternative splicing. Mol Cell 10(1):45–53

    Article  Google Scholar 

  71. Savkur RS, Philips AV, Cooper TA (2001) Aberrant regulation of insulin receptor alternative splicing is associated with insulin resistance in myotonic dystrophy. Nat Genet 29(1):40–47. https://doi.org/10.1038/ng704

    Article  CAS  PubMed  Google Scholar 

  72. Fugier C, Klein AF, Hammer C et al (2011) Misregulated alternative splicing of BIN1 is associated with T tubule alterations and muscle weakness in myotonic dystrophy. Nat Med 17(6):720–725. https://doi.org/10.1038/nm.2374

    Article  CAS  PubMed  Google Scholar 

  73. Rau F, Laine J, Ramanoudjame L et al (2015) Abnormal splicing switch of DMD's penultimate exon compromises muscle fibre maintenance in myotonic dystrophy. Nat Commun 6:7205. https://doi.org/10.1038/ncomms8205

    Article  PubMed  Google Scholar 

  74. Wheeler TM, Lueck JD, Swanson MS et al (2007) Correction of ClC-1 splicing eliminates chloride channelopathy and myotonia in mouse models of myotonic dystrophy. J Clin Invest 117(12):3952–3957. https://doi.org/10.1172/JCI33355

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Letter from Ionis Pharmaceuticals & Biogen to the MDF Community (2017.) http://us8.campaign-archive2.com/?u=8f5969cac3271759ce78c8354&id=1109538bcf&e=[UNIQID]. Accessed Sep 2017

    Google Scholar 

  76. Koebis M, Kiyatake T, Yamaura H et al (2013) Ultrasound-enhanced delivery of morpholino with bubble liposomes ameliorates the myotonia of myotonic dystrophy model mice. Sci Rep 3:2242. https://doi.org/10.1038/srep02242

    Article  PubMed  PubMed Central  Google Scholar 

  77. Anderson LV, Davison K, Moss JA et al (1999) Dysferlin is a plasma membrane protein and is expressed early in human development. Hum Mol Genet 8(5):855–861

    Article  CAS  PubMed  Google Scholar 

  78. Glover L, Brown RH Jr (2007) Dysferlin in membrane trafficking and patch repair. Traffic 8(7):785–794. https://doi.org/10.1111/j.1600-0854.2007.00573.x

    Article  CAS  PubMed  Google Scholar 

  79. Aoki M (2004) Dysferlinopathy. GeneReviews®, Seattle (WA). University of Washington, Seattle, pp 1993–2017

    Google Scholar 

  80. Liu J, Aoki M, Illa I et al (1998) Dysferlin, a novel skeletal muscle gene, is mutated in Miyoshi myopathy and limb girdle muscular dystrophy. Nat Genet 20(1):31–36. https://doi.org/10.1038/1682

    Article  CAS  PubMed  Google Scholar 

  81. Illa I, Serrano-Munuera C, Gallardo E et al (2001) Distal anterior compartment myopathy: a dysferlin mutation causing a new muscular dystrophy phenotype. Ann Neurol 49(1):130–134

    Article  CAS  PubMed  Google Scholar 

  82. Patel NJ, Van Dyke KW, Espinoza LR (2017) Limb-girdle muscular dystrophy 2B and Miyoshi presentations of dysferlinopathy. Am J Med Sci 353(5):484–491. https://doi.org/10.1016/j.amjms.2016.05.024

    Article  PubMed  Google Scholar 

  83. Lee JJA, Maruyama R, Sakurai H et al (2018) Cell membrane repair assay using a two-photon laser microscope. J Vis Exp 131:e56999–e56999. https://doi.org/10.3791/56999

    Article  CAS  Google Scholar 

  84. Sinnreich M, Therrien C, Karpati G (2006) Lariat branch point mutation in the dysferlin gene with mild limb-girdle muscular dystrophy. Neurology 66(7):1114–1116. https://doi.org/10.1212/01.wnl.0000204358.89303.81

    Article  PubMed  Google Scholar 

  85. Aartsma-Rus A, Singh KH, Fokkema IF et al (2010) Therapeutic exon skipping for dysferlinopathies? Eur J Hum Genet 18(8):889–894. https://doi.org/10.1038/ejhg.2010.4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Barthelemy F, Blouin C, Wein N et al (2015) Exon 32 skipping of dysferlin rescues membrane repair in patients' cells. J Neuromuscul Dis 2(3):281–290. https://doi.org/10.3233/JND-150109

    Article  PubMed  PubMed Central  Google Scholar 

  87. Durbeej M (2015) Laminin-alpha2 chain-deficient congenital muscular dystrophy: pathophysiology and development of treatment. Curr Top Membr 76:31–60. https://doi.org/10.1016/bs.ctm.2015.05.002

    Article  PubMed  Google Scholar 

  88. Collins J, Bonnemann CG (2010) Congenital muscular dystrophies: toward molecular therapeutic interventions. Curr Neurol Neurosci Rep 10(2):83–91. https://doi.org/10.1007/s11910-010-0092-8

    Article  CAS  PubMed  Google Scholar 

  89. Zhang X, Vuolteenaho R, Tryggvason K (1996) Structure of the human laminin alpha2-chain gene (LAMA2), which is affected in congenital muscular dystrophy. J Biol Chem 271(44):27664–27669

    Article  CAS  PubMed  Google Scholar 

  90. Siala O, Louhichi N, Triki C et al (2007) Severe MDC1A congenital muscular dystrophy due to a splicing mutation in the LAMA2 gene resulting in exon skipping and significant decrease of mRNA level. Genet Test 11(3):199–207. https://doi.org/10.1089/gte.2006.0517

    Article  CAS  PubMed  Google Scholar 

  91. Aoki Y, Nagata T, Yokota T et al (2013) Highly efficient in vivo delivery of PMO into regenerating myotubes and rescue in laminin-alpha2 chain-null congenital muscular dystrophy mice. Hum Mol Genet 22(24):4914–4928. https://doi.org/10.1093/hmg/ddt341

    Article  CAS  PubMed  Google Scholar 

  92. Kimberling WJ, Hildebrand MS, Shearer AE et al (2010) Frequency of usher syndrome in two pediatric populations: implications for genetic screening of deaf and hard of hearing children. Genet Med 12(8):512–516. https://doi.org/10.1097/GIM.0b013e3181e5afb8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Yan D, Liu XZ (2010) Genetics and pathological mechanisms of usher syndrome. J Hum Genet 55(6):327–335. https://doi.org/10.1038/jhg.2010.29

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Millan JM, Aller E, Jaijo T et al (2011) An update on the genetics of usher syndrome. J Ophthalmol 417217:2011. https://doi.org/10.1155/2011/417217

    Article  CAS  Google Scholar 

  95. Vache C, Besnard T, le Berre P et al (2012) Usher syndrome type 2 caused by activation of an USH2A pseudoexon: implications for diagnosis and therapy. Hum Mutat 33(1):104–108. https://doi.org/10.1002/humu.21634

    Article  CAS  PubMed  Google Scholar 

  96. Slijkerman RW, Vache C, Dona M et al (2016) Antisense oligonucleotide-based splice correction for ush2a-associated retinal degeneration caused by a frequent deep-intronic mutation. Mol Ther Nucleic Acids 5(10):e381. https://doi.org/10.1038/mtna.2016.89

    Article  CAS  PubMed  Google Scholar 

  97. Therapeutics P (2017) Innovation programs. http://www.proqr.com/innovation-programs/. Accessed 25 Sep 2017

  98. Sakai LY, Keene DR, Morris NP et al (1986) Type VII collagen is a major structural component of anchoring fibrils. J Cell Biol 103(4):1577–1586

    Article  CAS  PubMed  Google Scholar 

  99. Turczynski S, Titeux M, Tonasso L et al (2016) Targeted exon skipping restores type VII collagen expression and anchoring fibril formation in an in vivo RDEB model. J Invest Dermatol 136(12):2387–2395. https://doi.org/10.1016/j.jid.2016.07.029

    Article  CAS  PubMed  Google Scholar 

  100. Murata T, Masunaga T, Ishiko A et al (2004) Differences in recurrent COL7A1 mutations in dystrophic epidermolysis bullosa: ethnic-specific and worldwide recurrent mutations. Arch Dermatol Res 295(10):442–447. https://doi.org/10.1007/s00403-003-0444-1

    Article  CAS  PubMed  Google Scholar 

  101. Gardella R, Castiglia D, Posteraro P et al (2002) Genotype-phenotype correlation in italian patients with dystrophic epidermolysis bullosa. J Invest Dermatol 119(6):1456–1462. https://doi.org/10.1046/j.1523-1747.2002.19606.x

    Article  CAS  PubMed  Google Scholar 

  102. Salas-Alanis JC, Amaya-Guerra M, McGrath JA (2000) The molecular basis of dystrophic epidermolysis bullosa in Mexico. Int J Dermatol 39(6):436–442

    Article  CAS  PubMed  Google Scholar 

  103. Csikos M, Szocs HI, Laszik A et al (2005) High frequency of the 425A-->G splice-site mutation and novel mutations of the COL7A1 gene in Central Europe: significance for future mutation detection strategies in dystrophic epidermolysis bullosa. Br J Dermatol 152(5):879–886. https://doi.org/10.1111/j.1365-2133.2005.06542.x

    Article  CAS  PubMed  Google Scholar 

  104. Tamai K, Murai T, Mayama M et al (1999) Recurrent COL7A1 mutations in Japanese patients with dystrophic epidermolysis bullosa: positional effects of premature termination codon mutations on clinical severity. Japanese collaborative study group on Epidermolysis Bullosa. J Invest Dermatol 112(6):991–993. https://doi.org/10.1046/j.1523-1747.1999.00601.x

    Article  CAS  PubMed  Google Scholar 

  105. Mohammedi R, Mellerio JE, Ashton GH et al (1999) A recurrent COL7A1 mutation, R2814X, in British patients with recessive dystrophic epidermolysis bullosa. Clin Exp Dermatol 24(1):37–39

    Article  CAS  PubMed  Google Scholar 

  106. Dang N, Murrell DF (2008) Mutation analysis and characterization of COL7A1 mutations in dystrophic epidermolysis bullosa. Exp Dermatol 17(7):553–568. https://doi.org/10.1111/j.1600-0625.2008.00723.x

    Article  CAS  PubMed  Google Scholar 

  107. Mellerio JE, Dunnill MG, Allison W et al (1997) Recurrent mutations in the type VII collagen gene (COL7A1) in patients with recessive dystrophic epidermolysis bullosa. J Invest Dermatol 109(2):246–249

    Article  CAS  PubMed  Google Scholar 

  108. Goto M, Sawamura D, Nishie W et al (2006) Targeted skipping of a single exon harboring a premature termination codon mutation: implications and potential for gene correction therapy for selective dystrophic epidermolysis bullosa patients. J Invest Dermatol 126(12):2614–2620. https://doi.org/10.1038/sj.jid.5700435

    Article  CAS  PubMed  Google Scholar 

  109. ProQR receives orphan drug designation from FDA for drug candidate QR-313 for dystrophic epidermolysis bullosa and will present data at two scientific conferences. (2017). https://globenewswire.com/news-release/2017/09/19/1124532/0/en/ProQR-Receives-Orphan-Drug-Designation-from-FDA-for-Drug-Candidate-QR-313-for-Dystrophic-Epidermolysis-Bullosa-and-will-Present-Data-at-two-Scientific-Conferences.html. Accessed Sep 2017

  110. N.V PT (2017). http://www.proqr.com/qr-313-for-dystrophic-epidermolysis-bullosa/. Accessed Sep 2017

  111. Galli SJ, Tsai M, Piliponsky AM (2008) The development of allergic inflammation. Nature 454(7203):445–454. https://doi.org/10.1038/nature07204

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Brown JM, Wilson TM, Metcalfe DD (2008) The mast cell and allergic diseases: role in pathogenesis and implications for therapy. Clin Exp Allergy 38(1):4–18. https://doi.org/10.1111/j.1365-2222.2007.02886.x

    Article  CAS  PubMed  Google Scholar 

  113. Gilfillan AM, Tkaczyk C (2006) Integrated signalling pathways for mast-cell activation. Nat Rev Immunol 6(3):218–230. https://doi.org/10.1038/nri1782

    Article  CAS  PubMed  Google Scholar 

  114. Ishibashi K, Suzuki M, Sasaki S et al (2001) Identification of a new multigene four-transmembrane family (MS4A) related to CD20, HTm4 and beta subunit of the high-affinity IgE receptor. Gene 264(1):87–93

    Article  CAS  PubMed  Google Scholar 

  115. Cruse G, Kaur D, Leyland M et al (2010) A novel FcepsilonRIbeta-chain truncation regulates human mast cell proliferation and survival. FASEB J 24(10):4047–4057. https://doi.org/10.1096/fj.10-158378

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Ra C, Jouvin MH, Kinet JP (1989) Complete structure of the mouse mast cell receptor for IgE (fc epsilon RI) and surface expression of chimeric receptors (rat-mouse-human) on transfected cells. J Biol Chem 264(26):15323–15327

    CAS  PubMed  Google Scholar 

  117. Dombrowicz D, Lin S, Flamand V et al (1998) Allergy-associated FcRbeta is a molecular amplifier of IgE- and IgG-mediated in vivo responses. Immunity 8(4):517–529

    Article  CAS  PubMed  Google Scholar 

  118. Cruse G, Beaven MA, Ashmole I et al (2013) A truncated splice-variant of the FcepsilonRIbeta receptor subunit is critical for microtubule formation and degranulation in mast cells. Immunity 38(5):906–917. https://doi.org/10.1016/j.immuni.2013.04.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Donnadieu E, Jouvin MH, Rana S et al (2003) Competing functions encoded in the allergy-associated F(c)epsilonRIbeta gene. Immunity 18(5):665–674

    Article  CAS  PubMed  Google Scholar 

  120. Cruse G, Yin Y, Fukuyama T et al (2016) Exon skipping of FcepsilonRIbeta eliminates expression of the high-affinity IgE receptor in mast cells with therapeutic potential for allergy. Proc Natl Acad Sci U S A 113(49):14115–14120. https://doi.org/10.1073/pnas.1608520113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Pignolo RJ, Kaplan FS (2017) Clinical staging of fibrodysplasia ossificans progressiva (FOP). Bone 109:111–114. https://doi.org/10.1016/j.bone.2017.09.014

    Article  PubMed  Google Scholar 

  122. Kaplan FS, Chakkalakal SA, Shore EM (2012) Fibrodysplasia ossificans progressiva: mechanisms and models of skeletal metamorphosis. Dis Model Mech 5(6):756–762. https://doi.org/10.1242/dmm.010280

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Miao J, Zhang C, Wu S et al (2012) Genetic abnormalities in fibrodysplasia ossificans progressiva. Genes Genet Syst 87(4):213–219

    Article  CAS  PubMed  Google Scholar 

  124. Shi S, Cai J, de Gorter DJ et al (2013) Antisense-oligonucleotide mediated exon skipping in activin-receptor-like kinase 2: inhibiting the receptor that is overactive in fibrodysplasia ossificans progressiva. PLoS One 8(7):e69096. https://doi.org/10.1371/journal.pone.0069096

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Shore EM, Xu M, Feldman GJ et al (2006) A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva. Nat Genet 38(5):525–527. https://doi.org/10.1038/ng1783

    Article  CAS  PubMed  Google Scholar 

  126. van Dinther M, Visser N, de Gorter DJ et al (2010) ALK2 R206H mutation linked to fibrodysplasia ossificans progressiva confers constitutive activity to the BMP type I receptor and sensitizes mesenchymal cells to BMP-induced osteoblast differentiation and bone formation. J Bone Miner Res 25(6):1208–1215. https://doi.org/10.1359/jbmr.091110

    Article  PubMed  Google Scholar 

  127. Kaplan FS, Xu M, Seemann P et al (2009) Classic and atypical fibrodysplasia ossificans progressiva (FOP) phenotypes are caused by mutations in the bone morphogenetic protein (BMP) type I receptor ACVR1. Hum Mutat 30(3):379–390. https://doi.org/10.1002/humu.20868

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Lounev VY, Ramachandran R, Wosczyna MN et al (2009) Identification of progenitor cells that contribute to heterotopic skeletogenesis. J Bone Joint Surg Am 91(3):652–663. https://doi.org/10.2106/JBJS.H.01177

    Article  PubMed  PubMed Central  Google Scholar 

  129. Medici D, Shore EM, Lounev VY et al (2010) Conversion of vascular endothelial cells into multipotent stem-like cells. Nat Med 16(12):1400–1406. https://doi.org/10.1038/nm.2252

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Shi S, de Gorter DJ, Hoogaars WM et al (2013) Overactive bone morphogenetic protein signaling in heterotopic ossification and Duchenne muscular dystrophy. Cell Mol Life Sci 70(3):407–423. https://doi.org/10.1007/s00018-012-1054-x

    Article  CAS  PubMed  Google Scholar 

  131. Leblanc E, Trensz F, Haroun S et al (2011) BMP-9-induced muscle heterotopic ossification requires changes to the skeletal muscle microenvironment. J Bone Miner Res 26(6):1166–1177. https://doi.org/10.1002/jbmr.311

    Article  CAS  PubMed  Google Scholar 

  132. Dang ZC, van Bezooijen RL, Karperien M et al (2002) Exposure of KS483 cells to estrogen enhances osteogenesis and inhibits adipogenesis. J Bone Miner Res 17(3):394–405. https://doi.org/10.1359/jbmr.2002.17.3.394

    Article  CAS  PubMed  Google Scholar 

  133. de Gorter DJ, van Dinther M, Korchynskyi O et al (2011) Biphasic effects of transforming growth factor beta on bone morphogenetic protein-induced osteoblast differentiation. J Bone Miner Res 26(6):1178–1187. https://doi.org/10.1002/jbmr.313

    Article  CAS  PubMed  Google Scholar 

  134. Guncay A, Yokota T (2015) Antisense oligonucleotide drugs for Duchenne muscular dystrophy: how far have we come and what does the future hold? Future Med Chem 7(13):1631–1635. https://doi.org/10.4155/fmc.15.116

    Article  CAS  PubMed  Google Scholar 

  135. Khorkova O, Wahlestedt C (2017) Oligonucleotide therapies for disorders of the nervous system. Nat Biotechnol 35(3):249–263. https://doi.org/10.1038/nbt.3784

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Goyenvalle A, Leumann C, Garcia L (2016) Therapeutic potential of Tricyclo-DNA antisense oligonucleotides. J Neuromuscul Dis 3(2):157–167. https://doi.org/10.3233/JND-160146

    Article  PubMed  PubMed Central  Google Scholar 

  137. Goyenvalle A, Griffith G, Babbs A et al (2015) Functional correction in mouse models of muscular dystrophy using exon-skipping tricyclo-DNA oligomers. Nat Med 21(3):270–275. https://doi.org/10.1038/nm.3765

    Article  CAS  PubMed  Google Scholar 

  138. Relizani K, Griffith G, Echevarria L et al (2017) Efficacy and safety profile of tricyclo-DNA antisense oligonucleotides in duchenne muscular dystrophy mouse model. Mol Ther Nucleic Acids 8:144–157. https://doi.org/10.1016/j.omtn.2017.06.013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Cao L, Han G, Lin C et al (2016) Fructose promotes uptake and activity of oligonucleotides with different chemistries in a context-dependent manner in mdx mice. Mol Ther Nucleic Acids 5(6):e329. https://doi.org/10.1038/mtna.2016.46

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Han G, Gu B, Cao L et al (2016) Hexose enhances oligonucleotide delivery and exon skipping in dystrophin-deficient mdx mice. Nat Commun 7:10981. https://doi.org/10.1038/ncomms10981

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Coley WD, Bogdanik L, Vila MC et al (2016) Effect of genetic background on the dystrophic phenotype in mdx mice. Hum Mol Genet 25(1):130–145. https://doi.org/10.1093/hmg/ddv460

    Article  CAS  PubMed  Google Scholar 

  142. Fukada S, Morikawa D, Yamamoto Y et al (2010) Genetic background affects properties of satellite cells and mdx phenotypes. Am J Pathol 176(5):2414–2424. https://doi.org/10.2353/ajpath.2010.090887

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Rodrigues M, Echigoya Y, Fukada S et al (2016) Current translational research and murine models for duchenne muscular dystrophy. J Neuromuscul Dis 3(1):29–48

    Article  PubMed  PubMed Central  Google Scholar 

  144. Rodrigues M, Echigoya Y, Maruyama R et al (2016) Impaired regenerative capacity and lower revertant fibre expansion in dystrophin-deficient mdx muscles on DBA/2 background. Sci Rep 6:38371. https://doi.org/10.1038/srep38371

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Nakamura A, Fueki N, Shiba N et al (2016) Deletion of exons 3-9 encompassing a mutational hot spot in the DMD gene presents an asymptomatic phenotype, indicating a target region for multiexon skipping therapy. J Hum Genet 61(7):663–667. https://doi.org/10.1038/jhg.2016.28

    Article  CAS  PubMed  Google Scholar 

  146. Echigoya Y, Yokota T (2014) Skipping multiple exons of dystrophin transcripts using cocktail antisense oligonucleotides. Nucleic Acid Ther 24(1):57–68. https://doi.org/10.1089/nat.2013.0451

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the Friends of Garrett Cumming Research Chair Fund, the HM Toupin Neurological Science Research Chair Fund, the Muscular Dystrophy Canada, Canada Foundation for Innovation (CFI), Alberta Advanced Education and Technology (AET), Canadian Institutes of Health Research (CIHR), Jesse’s Journey - The Foundation for Gene and Cell Therapy, the University of Alberta Faculty of Medicine and Dentistry, and the Women and Children’s Health Research Institute (WCHRI).

Author information

Authors and Affiliations

  1. Department of Medical Genetics, University of Alberta Faculty of Medicine and Dentistry, Edmonton, AB, Canada

    Merryl Rodrigues & Toshifumi Yokota

  2. The Friends of Garrett Cumming Research and Muscular Dystrophy Canada HM Toupin Neurological Science Endowed Research Chair, Edmonton, AB, Canada

    Toshifumi Yokota

Authors
  1. Merryl Rodrigues
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Toshifumi Yokota
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Toshifumi Yokota .

Editor information

Editors and Affiliations

  1. Medical Genetics, University of Alberta, Edmonton, AB, Canada

    Toshifumi Yokota

  2. Medical Genetics, University of Alberta, Edmonton, AB, Canada

    Rika Maruyama

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer Science+Business Media, LLC, part of Springer Nature

About this protocol

Check for updates. Verify currency and authenticity via CrossMark

Cite this protocol

Rodrigues, M., Yokota, T. (2018). An Overview of Recent Advances and Clinical Applications of Exon Skipping and Splice Modulation for Muscular Dystrophy and Various Genetic Diseases. In: Yokota, T., Maruyama, R. (eds) Exon Skipping and Inclusion Therapies. Methods in Molecular Biology, vol 1828. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-8651-4_2

Download citation

  • DOI: https://doi.org/10.1007/978-1-4939-8651-4_2

  • Published:

  • Publisher Name: Humana Press, New York, NY

  • Print ISBN: 978-1-4939-8650-7

  • Online ISBN: 978-1-4939-8651-4

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation