Exon skipping and Duchenne muscular dystrophy: Hope, hype and how feasible?

Neurology India

Volumn 56, Issue 3, 2008, Pages 254-262

  Wilton, Steve ^a   Fletcher, Susan ^a  

^a UNIVERSITY OF WESTERN AUSTRALIA   (Australia)

Author keywords

Becker muscular dystrophy; Clinical trials; Duchenne muscular dystrophy; Exon skipping; Morpholino oligomer; Personalized genetic medicines

Indexed keywords

OLIGOMER;

DUCHENNE MUSCULAR DYSTROPHY; EXON; GENE DELETION; GENE MUTATION; GENE TARGETING; GENETIC TRANSCRIPTION; REVIEW;

ANIMALS; CLINICAL TRIALS AS TOPIC; DYSTROPHIN; EXONS; GENE THERAPY; HUMANS; MUSCULAR DYSTROPHY, DUCHENNE; RNA, MESSENGER; SEQUENCE DELETION;

EID: 56049083502     PISSN: 00283886     EISSN: 19984022     Source Type: Journal    
DOI: 10.4103/0028-3886.43443     Document Type: Review

References (98)

1. Koenig M, Hoffman EP, Bertelson CJ, Monaco AP, Feener C, Kunkel LM. Complete cloning of the Duchenne muscular dystrophy (DMD) cDNA and preliminary genomic organization of the DMD gene in normal and affected individuals. Cell 1987;50:509-17.
2. Emery AE. Clinical and molecular studies in Duchenne muscular dystrophy. Prog Clin Biol Res 1989;306:15-28.
3. Emery AE. The muscular dystrophies. Lancet 2002;359:687-95.
4. Prior TW, Bridgeman SJ. Experience and strategy for the molecular testing of Duchenne muscular dystrophy. J Mol Diagn 2005;7:317-26.
5. Eagle M, Baudouin SV, Chandler C, Giddings DR, Bullock R, Bushby K. Survival in Duchenne muscular dystrophy: Improvements in life expectancy since 1967 and the impact of home nocturnal ventilation. Neuromuscul Disord 2002;12:926-9.
6. Beggs AH, Hoffman EP, Snyder JR, Arahata K, Specht L, Shapiro F, et al. Exploring the molecular basis for variability among patients with Becker muscular dystrophy: dystrophin gene and protein studies. Am J Hum Genet 1991;49:54-67.
7. Comi GP, Prelle A, Bresolin N, Moggio M, Bardoni A, Gallanti A, et al. Clinical variability in Becker muscular dystrophy: Genetic, biochemical and immunohistochemical correlates. Brain 1994;117:1-14.
8. Schwartz M, Duno M, Palle AL, Krag T, Vissing J. Deletion of exon 16 of the dystrophin gene is not associated with disease. Hum Mutat 2007;28:205.
9. Monaco AP, Bertelson CJ, Liechti-Gallati S, Moser H, Kunkel LM. An explanation for the phenotypic differences between patients bearing partial deletions of the DMD locus. Genomics 1988;2:90-5.
10. Koenig M, Beggs AH, Moyer M, Scherpf S, Heindrich K, Bettecken T, et al. The molecular basis for Duchenne versus Becker muscular dystrophy: Correlation of severity with type of deletion. Am J Hum Genet 1989;45:498-506.
11. Morandi L, Mora M, Confalonieri V, Barresi R, Di Blasi C, Brugnoni R, et al. Dystrophin characterization in BMD patients: Correlation of abnormal protein with clinical phenotype. J Neurol Sci 1995;132:146-55.
12. Muntoni F, Gobbi P, Sewry C, Sherratt T, Taylor J, Sandhu SK, et al. Deletions in the 5′ region of dystrophin and resulting phenotypes. J Med Genet 1994;31:843-7.
13. Novakovic I, Bojic D, Todorovic S, Apostolski S, Lukovic L, Stefanovic D, et al. Proximal dystrophin gene deletions and protein alterations in Becker muscular dystrophy. Ann N Y Acad Sci 2005;1048:406-10.
14. Beroud C, Tuffery-Giraud S, Matsuo M, Hamroun D, Humbertclaude V, Monnier N, et al. 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 2007;28:196-202.
15. Nakamura A, Yoshida K, Fukushima K, Ueda H, Urasawa N, Koyama J, et al. Follow-up of three patients with a large in-frame deletion of exons 45-55 in the Duchenne muscular dystrophy (DMD) gene. J Clin Neurosci 2008;15:757-63.
16. Fanin M, Freda MP, Vitiello L, Danieli GA, Pegoraro E, Angelini C. Duchenne phenotype with in-frame deletion removing major portion of dystrophin rod: Threshold effect for deletion size? Muscle Nerve 1996;19:1154-60.
17. Chamberlain JS, Corrado K, Rafael JA, Cox GA, Hauser M, Lumeng C. Interactions between dystrophin and the sarcolemma membrane. Soc Gen Physiol Ser 1997;52:19-29.
18. Fanin M, Danieli GA, Cadaldini M, Miorin M, Vitiello L, Angelini C. Dystrophin-positive fibers in Duchenne dystrophy: Origin and correlation to clinical course. Muscle Nerve 1995;18:1115-20.
19. Fanin M, Danieli GA, Vitiello L, Senter L, Angelini C. Prevalence of dystrophin-positive fibers in 85 Duchenne muscular dystrophy patients. Neuromuscul Disord 1992;2:41-5.
20. Sherratt TG, Vulliamy T, Dubowitz V, Sewry CA, Strong PN. Exon skipping and translation in patients with frameshift deletions in the dystrophin gene. Am J Hum Genet 1993;53:1007-15.
21. Schatzberg SJ, Anderson LV, Wilton SD, Kornegay JN, Mann CJ, Solomon GG, et al. Alternative dystrophin gene transcripts in golden retriever muscular dystrophy. Muscle Nerve 1998;21:991-8.
22. Wilton SD, Dye DE, Blechynden LM, Laing NG. Revertant fibres: A possible genetic therapy for Duchenne muscular dystrophy? Neuromuscul Disord. 1997;7:329-35.
23. Wilton SD, Dye DE, Laing NG. Dystrophin gene transcripts skipping the mdx mutation. Muscle Nerve 1997;20:728-34.
24. Lu QL, Morris GE, Wilton SD, Ly T, Artemyeva OV, Strong P, et al. Massive idiosyncratic exon skipping corrects the nonsense mutation in dystrophic mouse muscle and produces functional revertant fibers by clonal expansion. J Cell Biol 2000;148:985-96.
25. Koenig M, Monaco AP, Kunkel LM. The complete sequence of dystrophin predicts a rod-shaped cytoskeletal protein. Cell 1988;53:219-28.
26. Roberts RG, Coffey AJ, Bobrow M, Bentley DR. Exon structure of the human dystrophin gene. Genomics 1993;16:536-8.
27. England SB, Nicholson LV, Johnson MA, Forrest SM, Love DR, Zubrzycka-Gaarn EE, et al. Very mild muscular dystrophy associated with the deletion of 46% of dystrophin. Nature 1990;343:180-2.
28. Odom GL, Gregorevic P, Chamberlain JS. Viral-mediated gene therapy for the muscular dystrophies: Successes, limitations and recent advances. Biochim Biophys Acta 2007;1772:243-62.
29. Yuasa K, Yoshimura M, Urasawa N, Ohshima S, Howell JM, Nakamura A, et al. Injection of a recombinant AAV serotype 2 into canine skeletal muscles evokes strong immune responses against transgene products. Gene Ther 2007;14:1249-60.
30. Gregorevic P, Allen JM, Minami E, Blankinship MJ, Haraguchi M, Meuse L, et al. rAAV6-microdystrophin preserves muscle function and extends lifespan in severely dystrophic mice. Nat Med 2006;12:787-9.
31. Corrado K, Mills PL, Chamberlain JS. Deletion analysis of the dystrophin-actin binding domain. FEBS Lett 1994;344:255-60.
32. Banks GB, Gregorevic P, Allen JM, Finn EE, Chamberlain JS. Functional capacity of dystrophins carrying deletions in the N-terminal actin-binding domain. Hum Mol Genet 2007;16:2105-13.
33. Monaco AP. Dystrophin, the protein product of the Duchenne/Becker muscular dystrophy gene. Trends Biochem Sci 1989;14:412-5.
34. Tennyson CN, Klamut HJ, Worton RG. The human dystrophin gene requires 16 hours to be transcribed and is cotranscriptionally spliced. Nat Genet 1995;9:184-90.
35. Chelly J, Kaplan JC, Maire P, Gautron S, Kahn A. Transcription of the dystrophin gene in human muscle and non-muscle tissue. Nature 1988;333:858-60.
36. Den Dunnen JT, Grootscholten PM, Bakker E, Blonden LA, Ginjaar HB, Wapenaar MC, et al. Topography of the Duchenne muscular dystrophy (DMD) gene: FIGE and cDNA analysis of 194 cases reveals 115 deletions and 13 duplications. Am J Hum Genet. 1989;45:835-47.
37. Dominski Z, Kole R. Restoration of correct splicing in thalassemic pre-mRNA by antisense oligonucleotides. Proc Natl Acad Sci USA 1993;90:8673-7.
38. Kornegay JN, Tuler SM, Miller DM, Levesque DC. Muscular dystrophy in a litter of golden retriever dogs. Muscle Nerve 1988;11:1056-64.
39. Sharp NJ, Kornegay JN, Van Camp SD, Herbstreith MH, Secore SL, Kettle S, et al. An error in dystrophin mRNA processing in golden retriever muscular dystrophy, an animal homologue of Duchenne muscular dystrophy. Genomics 1992;13:115-21.
40. Fletcher S, Ly T, Duff RM, Mc CH, Wilton SD. Cryptic splicing involving the splice site mutation in the canine model of Duchenne muscular dystrophy. Neuromuscul Disord 2001;11:239-43.
41. Wilton SD, Chandler DC, Kakulas BA, Laing NG. Identification of a point mutation and germinal mosaicism in a Duchenne muscular dystrophy family. Hum Mutat 1994;3:133-40.
42. Takeshima Y, Nishio H, Sakamoto H, Nakamura H, Matsuo M. Modulation of in vitro splicing of the upstream intron by modifying an intra-exon sequence which is deleted from the dystrophin gene in dystrophin Kobe. J Clin Invest 1995;95:515-20.
43. Pramono ZA, Takeshima Y, Alimsardjono H, Ishii A, Takeda S, Matsuo M. Induction of exon skipping of the dystrophin transcript in lymphoblastoid cells by transfecting an antisense oligodeoxynucleotide complementary to an exon recognition sequence. Biochem Biophys Res Commun 1996;226:445-9.
44. Matsuo M, Masumura T, Nakajima T, Kitoh Y, Takumi T, Nishio H, et al. A very small frame-shifting deletion within exon 19 of the Duchenne muscular dystrophy gene. Biochem Biophys Res Commun 1990;170:963-7.
45. Matsuo M, Masumura T, Nishio H, Nakajima T, Kitoh Y, Takumi T, et al. Exon skipping during splicing of dystrophin mRNA precursor due to an intraexon deletion in the dystrophin gene of Duchenne muscular dystrophy kobe. J Clin Invest 1991;87:2127-31.
46. Aartsma-Rus A, Bremmer-Bout M, Janson AA, den Dunnen JT, van Ommen GJ, van Deutekom JC. Targeted exon skipping as a potential gene correction therapy for Duchenne muscular dystrophy. Neuromuscul Disord 2002;12:S71-7.
47. Aartsma-Rus A, De Winter CL, Janson AA, Kaman WE, Van Ommen GJ, Den Dunnen JT, et al. Functional analysis of 114 exon-internal AONs for targeted DMD exon skipping: Indication for steric hindrance of SR protein binding sites. Oligonucleotides 2005;15:284-97.
48. Aartsma-Rus A, Janson AA, Heemskerk JA, De Winter CL, Van Ommen GJ, Van Deutekom JC. Therapeutic modulation of DMD splicing by blocking exonic splicing enhancer sites with antisense oligonucleotides. Ann N Y Acad Sci 2006;1082:74-6.
49. Aartsma-Rus A, Janson AA, Kaman WE, Bremmer-Bout M, den Dunnen JT, Baas F, et al. Therapeutic antisense-induced exon skipping in cultured muscle cells from six different DMD patients. Hum Mol Genet 2003;12:907-14.
50. Aartsma-Rus A, Janson AA, Kaman WE, Bremmer-Bout M, van Ommen GJ, den Dunnen JT, et al. Antisense-induced multiexon skipping for Duchenne muscular dystrophy makes more sense. Am J Hum Genet 2004;74:83-92.
51. Aartsma-Rus A, van Ommen GJ. Antisense-mediated exon skipping: A versatile tool with therapeutic and research applications. RNA 2007;13:1609-24.
52. Bulfield G, Siller WG, Wight PA, Moore KJ. X chromosome-linked muscular dystrophy (mdx) in the mouse. Proc Natl Acad Sci USA 1984;81:1189-92.
53. Sicinski P, Geng Y, Ryder-Cook AS, Barnard EA, Darlison MG, Barnard PJ. The molecular basis of muscular dystrophy in the mdx mouse: A point mutation. Science 1989;244:1578-80.
54. Stedman HH, Sweeney HL, Shrager JB, Maguire HC, Panettieri RA, Petrof B, et al. The mdx mouse diaphragm reproduces the degenerative changes of Duchenne muscular dystrophy. Nature 1991;352:536-9.
55. Wilton SD, Lloyd F, Carville K, Fletcher S, Honeyman K, Agrawal S, et al. Specific removal of the nonsense mutation from the mdx dystrophin mRNA using antisense oligonucleotides. Neuromuscul Disord 1999;9:330-8.
56. Mann CJ, Honeyman K, Cheng AJ, Ly T, Lloyd F, Fletcher S, et al. Antisense-induced exon skipping and synthesis of dystrophin in the mdx mouse. Proc Natl Acad Sci USA 2001;98:42-7.
57. Mann CJ, Honeyman K, McClorey G, Fletcher S, Wilton SD. Improved antisense oligonucleotide induced exon skipping in the mdx mouse model of muscular dystrophy. J Gene Med 2002;4:644-54.
58. Lu QL, Mann CJ, Lou F, Bou-Gharios G, Morris GE, Xue SA, et al. Functional amounts of dystrophin produced by skipping the mutated exon in the mdx dystrophic mouse. Nat Med 2003;9:1009-14.
59. Sirsi SR, Williams JH, Lutz GJ. Poly(ethylene imine)-poly(ethylene glycol) copolymers facilitate efficient delivery of antisense oligonucleotides to nuclei of mature muscle cells of mdx mice. Hum Gene Ther 2005;16:1307-17.
60. Williams JH, Sirsi SR, Latta DR, Lutz GJ. Induction of dystrophin expression by exon skipping in mdx mice following intramuscular injection of antisense oligonucleotides complexed with PEG-PEI copolymers. Mol Ther 2006;14:88-96.
61. Wells KE, Fletcher S, Mann CJ, Wilton SD, Wells DJ. Enhanced in vivo delivery of antisense oligonucleotides to restore dystrophin expression in adult mdx mouse muscle. FEBS Lett 2003;552:145-9.
62. Rando TA. Non-viral gene therapy for Duchenne muscular dystrophy: progress and challenges. Biochim Biophys Acta 2007;1772:263-71.
63. Crooke ST. Molecular mechanisms of action of antisense drugs. Biochim Biophys Acta 1999;1489:31-44.
64. Aartsma-Rus A, Kaman WE, Bremmer-Bout M, Janson AA, den Dunnen JT, van Ommen GJ, et al. Comparative analysis of antisense oligonucleotide analogs for targeted DMD exon 46 skipping in muscle cells. Gene Ther 2004;11:1391-8.
65. Sazani P, Gemignani F, Kang SH, Maier MA, Manoharan M, Persmark M, et al. Systemically delivered antisense oligomers upregulate gene expression in mouse tissues. Nat Biotechnol 2002;20:1228-33.
66. Yin H, Lu Q, Wood M. Effective exon skipping and restoration of dystrophin expression by peptide nucleic acid antisense oligonucleotides in mdx mice. Mol Ther 2008;16:38-45.
67. Braasch DA, Liu Y, Corey DR. Antisense inhibition of gene expression in cells by oligonucleotides incorporating locked nucleic acids: Effect of mRNA target sequence and chimera design. Nucleic Acids Res 2002;30:5160-7.
68. Fletcher S, Honeyman K, Fall AM, Harding PL, Johnsen RD, Wilton SD. Dystrophin expression in the mdx mouse after localised and systemic administration of a morpholino antisense oligonucleotide. J Gene Med 2006;8:207-16.
69. Gebski BL, Mann CJ, Fletcher S, Wilton SD. Morpholino antisense oligonucleotide induced dystrophin exon 23 skipping in mdx mouse muscle. Hum Mol Genet 2003;12:1801-11.
70. Schmajuk G, Sierakowska H, Kole R. Antisense oligonucleotides with different backbones. Modification of splicing pathways and efficacy of uptake. J Biol Chem 1999;274:21783-9.
71. Muntoni F, Mateddu A, Marchei F, Clerk A, Serra G. Muscular weakness in the mdx mouse. J Neurol Sci 1993;120:71-7.
72. Alter J, Lou F, Rabinowitz A, Yin H, Rosenfeld J, Wilton SD, et al. Systemic delivery of morpholino oligonucleotide restores dystrophin expression bodywide and improves dystrophic pathology. Nat Med 2006;12:175-7.
73. Fletcher S, Honeyman K, Fall AM, Harding PL, Johnsen RD, Steinhaus JP, et al. Morpholino oligomer-mediated exon skipping averts the onset of dystrophic pathology in the mdx mouse. Mol Ther 2007;15:1587-92.
74. Moulton HM, Fletcher S, Neuman BW, McClorey G, Stein DA, Abes S, et al. Cell-penetrating peptide-morpholino conjugates alter pre-mRNA splicing of DMD (Duchenne muscular dystrophy) and inhibit murine coronavirus replication in vivo. Biochem Soc Trans 2007;35:826-8.
75. McClorey G, Fall AM, Moulton HM, Iversen PL, Rasko JE, Ryan M, et al. Induced dystrophin exon skipping in human muscle explants. Neuromuscul Disord 2006;16:583-90.
76. McClorey G, Moulton HM, Iversen PL, Fletcher S, Wilton SD. Antisense oligonucleotide-induced exon skipping restores dystrophin expression in vitro in a canine model of DMD. Gene Ther 2006;13:1373-81.
77. Im WB, Phelps SF, Copen EH, Adams EG, Slightom JL, Chamberlain JS. Differential expression of dystrophin isoforms in strains of mdx mice with different mutations. Hum Mol Genet 1996;5:1149-53.
78. Jearawiriyapaisarn N, Moulton HM, Buckley B, Roberts J, Sazani P, Fucharoen S, et al. Sustained dystrophin expression induced by peptide-conjugated morpholino oligomers in the muscles of mdx Mice. Mol Ther 2008; In press.
79. Wilton SD, Fall AM, Harding PL, McClorey G, Coleman C, Fletcher S. Antisense oligonucleotide-induced exon skipping across the human dystrophin gene transcript. Mol Ther 2007;15:1288-96.
80. Errington SJ, Mann CJ, Fletcher S, Wilton SD. Target selection for antisense oligonucleotide induced exon skipping in the dystrophin gene. J Gene Med 2003;5:518-27.
81. Harding PL, Fall AM, Honeyman K, Fletcher S, Wilton SD. The influence of antisense oligonucleotide length on dystrophin exon skipping. Mol Ther 2006;15:157-66.
82. Aartsma-Rus A, Kaman WE, Weij R, den Dunnen JT, van Ommen GJ, van Deutekom JC. Exploring the frontiers of therapeutic exon skipping for Duchenne muscular dystrophy by double targeting within one or multiple exons. Mol Ther 2006;14:401-7.
83. Adams AM, Harding PL, Iversen PL, Coleman C, Fletcher S, Wilton SD. Antisense oligonucleotide induced exon skipping and the dystrophin gene transcript: Cocktails and chemistries. BMC Mol Biol 2007;8:57.
84. Takeshima Y, Yagi M, Wada H, Ishibashi K, Nishiyama A, Kakumoto M, et al. Intravenous infusion of an antisense oligonucleotide results in exon skipping in muscle dystrophin mRNA of Duchenne muscular dystrophy. Pediatr Res 2006;59:690-4.
85. van Deutekom JC, Janson AA, Ginjaar IB, Frankhuizen WS, Aartsma-Rus A, Bremmer-Bout M, et al. Local dystrophin restoration with antisense oligonucleotide PRO051. N Engl J Med. 2007;357:2677-86.
86. Arechavala-Gomeza V, Graham IR, Popplewell LJ, Adams AM, Aartsma-Rus A, Kinali M, et al. Comparative analysis of antisense oligonucleotide sequences for targeted skipping of exon 51 during dystrophin Pre-mRNA splicing in human muscle. Hum Gene Ther 2007.
87. Aartsma-Rus A, Janson AA, van Ommen GJ, van Deutekom JC. Antisense-induced exon skipping for duplications in Duchenne muscular dystrophy. BMC Med Genet 2007;8:43.
88. Gurvich OL, Tuohy TM, Howard MT, Finkel RS, Medne L, Anderson CB, et al. DMD pseudoexon mutations: Splicing efficiency, phenotype and potential therapy. Ann Neurol 2008;63:81-9.
89. Madden H, Fletcher S, Davis M, Wilton SD. Characterisation of a complex DMD-causing dystrophin gene inversion and restoration of the reading frame by induced exon skipping. Hum Mutat 2008;in press.
90. Cole-Strauss A, Yoon K, Xiang Y, Byrne BC, Rice MC, Gryn J, et al. Correction of the mutation responsible for sickle cell anemia by an RNA-DNA oligonucleotide. Science 1996;273:1386-9.
91. Kmiec EB. Genomic targeting and genetic conversion in cancer therapy. Semin Oncol 1996;23:188-93.
92. Bertoni C, Lau C, Rando TA. Restoration of dystrophin expression in mdx muscle cells by chimeraplast-mediated exon skipping. Hum Mol Genet 2003;12:1087-99.
93. Kapsa RM, Quigley AF, Vadolas J, Steeper K, Ioannou PA, Byrne E, et al. Targeted gene correction in the mdx mouse using short DNA fragments: towards application with bone marrow-derived cells for autologous remodeling of dystrophic muscle. Gene Ther 2002;9:695-9.
94. Goyenvalle A, Vulin A, Fougerousse F, Leturcq F, Kaplan JC, Garcia L, et al. Rescue of dystrophic muscle through U7 snRNA-mediated exon skipping. Science 2004;306:1796-9.
95. Denti MA, Rosa A, D'Antona G, Sthandier O, De Angelis FG, Nicoletti C, et al. Body-wide gene therapy of Duchenne muscular dystrophy in the mdx mouse model. Proc Natl Acad Sci USA 2006;103:3758-63.
96. Denti MA, Rosa A, D'Antona G, Sthandier O, De Angelis FG, Nicoletti C, et al. Chimeric adeno-associated virus/antisense U1 small nuclear RNA effectively rescues dystrophin synthesis and muscle function by local treatment of mdx mice. Hum Gene Ther 2006;17:565-74.
97. Vulin A, Goyenvalle A, Barthelemy I, Leturcq F, Kaplan JC, Chelly J. Rescue of dystrophin in the GRMD dog by multiexon skipping using engineered U7 snRNAs. Neuromuscul Disord 2006;16:722-3.
98. Quenneville SP, Chapdelaine P, Skuk D, Paradis M, Goulet M, Rousseau J, et al. Autologous transplantation of muscle precursor cells modified with a lentivirus for muscular dystrophy: Human cells and primate models. Mol Ther 2007;15:431-8.