Ongoing therapeutic trials and outcome measures for Duchenne muscular dystrophy

Cellular and Molecular Life Sciences

Volumn 70, Issue 23, 2013, Pages 4585-4602

  Govoni, Alessandra ^a   Magri, Francesca ^a,b   Brajkovic, Simona ^a   Zanetta, Chiara ^a   Faravelli, Irene ^a   Corti, Stefania ^a   Bresolin, Nereo ^a,b   Comi, Giacomo P ^a  

^a UNIVERSITY OF MILAN   (Italy)

^b SCIENTIFIC INSTITUTE   (Italy)

Author keywords

Clinical trial; Duchenne muscular dystrophy; Exon skipping; New therapeutic approaches; Outcome measures; Readthrough

Indexed keywords

ADENOVIRUS VECTOR; ANTISENSE OLIGONUCLEOTIDE; ATALUREN; BIOLOGICAL MARKER; CORTICOSTEROID; CYCLOSPORIN A; DEFLAZACORT; DRISAPERSEN; DYSTROPHIN; ETEPLIRSEN; GIVINOSTAT; HISTONE DEACETYLASE INHIBITOR; IDEBENONE; MOLECULAR THERAPY AGENT; MORPHOLINO OLIGONUCLEOTIDE; NITRIC OXIDE; PLACEBO; PREDNISONE; PRO 044; SOMATOMEDIN C; TADALAFIL; UNCLASSIFIED DRUG;

BLOOD SAMPLING; CELL THERAPY; CLINICAL TRIAL (TOPIC); DOSAGE SCHEDULE COMPARISON; DOSE RESPONSE; DRUG DOSE ESCALATION; DRUG DOSE TITRATION; DRUG EFFICACY; DRUG INTERMITTENT THERAPY; DRUG MEGADOSE; DRUG SAFETY; DRUG TOLERABILITY; DUCHENNE MUSCULAR DYSTROPHY; EXON SKIPPING; GENE THERAPY; GLUCOSE INTOLERANCE; GROWTH RETARDATION; HUMAN; HYPERACTIVITY; HYPERTENSION; IMMUNE DEFICIENCY; IMMUNOMODULATION; INJECTION SITE PAIN; INJECTION SITE REACTION; LOW DRUG DOSE; MOTOR PERFORMANCE; MUSCLE BIOPSY; NONHUMAN; NUCLEAR MAGNETIC RESONANCE IMAGING; OSTEOPOROSIS; OUTCOME ASSESSMENT; OXIDATIVE STRESS; PHARMACEUTICAL CARE; PROTEINURIA; REVIEW; SINGLE DRUG DOSE; SKIN MANIFESTATION; STEROID THERAPY; VIRAL GENE DELIVERY SYSTEM;

ANIMALS; BIOLOGICAL MARKERS; CLINICAL TRIALS AS TOPIC; DRUG THERAPY; HUMANS; MUSCULAR DYSTROPHY, DUCHENNE; OUTCOME ASSESSMENT (HEALTH CARE); REPRODUCIBILITY OF RESULTS; STEM CELL TRANSPLANTATION; WALKING;

EID: 84889884673     PISSN: 1420682X     EISSN: 14209071     Source Type: Journal    
DOI: 10.1007/s00018-013-1396-z     Document Type: Review

References (104)

1. Emery AE (1991) Population frequencies of inherited neuromuscular diseases-a world survey. Neuromuscul Disord 1:19-29
2. Straub V, Campbell KP (1997) Muscular dystrophies and the dystrophin-glycoprotein complex. Curr Opin Neurol 10(2):168-175
3. De Palma C, Clementi E (2012) Nitric oxide in myogenesis and therapeutic muscle repair. Mol Neurobiol 46(3):682-692
4. Magri F, Govoni A, D'Angelo MG, Del Bo R, Ghezzi S, Sandra G, Turconi AC, Sciacco M, Ciscato P, Bordoni A, Tedeschi S, Fortunato F, Lucchini V, Bonato S, Lamperti C, Coviello D, Torrente Y, Corti S, Moggio M, Bresolin N, Comi GP (2011) Genotype and phenotype characterization in a large dystrophinopathic cohort with extended follow-up. J Neurol 258(9):1610-1623
5. Arechavala-Gomeza V, Kinali M, Feng L, Guglieri M, Edge G, Main M, Hunt D, Lehovsky J, Straub V, Bushby K, Sewry CA, Morgan JE, Muntoni F (2010) Revertant fibres and dystrophin traces in Duchenne muscular dystrophy: implication for clinical trials. Neuromuscul Disord 20(5):295-301
6. Davies KE, Smith TJ, Bundey S et al (1988) Mild and severe muscular dystrophy associated with deletions in Xp21 of the human X chromosome. J Med Genet 25:9-13
7. Beggs AH, Hoffman EP, Snyder JR et al (1991) Exploring the molecular basis for variability among patients with Becker muscular dystrophy: dystrophin gene and protein studies. Am J Hum Genet 49(1):54-67
8. Spurney CF (2011) Cardiomyopathy of Duchenne muscular dystrophy: current understanding and future directions. Muscle Nerve 44(1):8-19
9. Jefferies JL, Eidem BW, Belmont JW, Craigen WJ, Ware SM, Fernbach SD, Neish SR, Smith EO, Towbin JA (2005) Genetic predictors and remodeling of dilated cardiomyopathy in muscular dystrophy. Circulation 112(18):2799-2804
10. Politano L, Nigro G (2012) Treatment of dystrophinopathic cardiomyopathy: review of the literature and personal results. Acta Myol 31(1):24-30
11. Judge DP, Kass DA, Thompson WR, Wagner KR (2011) Pathophysiology and therapy of cardiac dysfunction in Duchenne muscular dystrophy. Am J Cardiovasc Drugs 11(5):287-294
12. Bushby K, Finkel R, Birnkrant DJ, Case LE, Clemens PR, Cripe L, Kaul A, Kinnett K, McDonald C, Pandya S, Poysky J, Shapiro F, Tomezsko J, Constantin C (2010) DMD care considerations working group. Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and pharmacological and psychosocial management. Lancet Neurol 9(1):77-93
13. Bushby K, Finkel R, Birnkrant DJ, Case LE, Clemens PR, Cripe L, Kaul A, Kinnett K, Pandya S, Poysky J, Shapiro F, Tomezsko J, Constantin C (2010) DMD care considerations working group. Diagnosis and management of Duchenne muscular dystrophy, part 2: implementation of multidisciplinary care. Lancet Neurol 9(2):177-189
14. Bushby K, Muntoni F, Urtizberea A, Hughes R, Griggs R (2004) Report on the 124th ENMC International Workshop. Treatment of Duchenne muscular dystrophy; defining the gold standards of management in the use of corticosteroids. Neuromuscul Disord 14(8-9):526-534
15. Bushby K, Connor E (2011) Clinical outcome measures for trials in Duchenne muscular dystrophy: report from International Working Group meetings. Clin Investig (Lond) 1(9):1217-1235
16. Mayhew JE, Florence JM, Mayhew TP, Henricson EK, Leshner RT, McCarter RJ, Escolar DM (2007) Reliable surrogate outcome measures in multicenter clinical trials of Duchenne muscular dystrophy. Muscle Nerve 35(1):36-42
17. Mazzone E, Vasco G, Sormani MP et al (2011) Functional changes in Duchenne muscular dystrophy: a 12-month longitudinal cohort study. Neurology 77(3):250-256
18. McDonald CM, Henricson EK, Han JJ, Abresch RT, Nicorici A, Atkinson L, Elfring GL, Reha A, Miller LL (2010) The 6MWT as a new outcome measure in Duchenne muscular dystrophy. Muscle Nerve 41(4):500-510
19. Mayhew A, Cano S, Scott E, Eagle M, Bushby K, Muntoni F (2011) North Star Clinical Network for Paediatric Neuromuscular Disease. Moving towards meaningful measurement: Rasch analysis of the North Star Ambulatory Assessment in Duchenne muscular dystrophy. Dev Med Child Neurol 53(6):535-542
20. Mazzone E, Martinelli D, Berardinelli A et al (2010) North Star Ambulatory Assessment, 6-minute walk test and timed items in ambulant boys with Duchenne muscular dystrophy. Neuromuscul Disord 20(11):712-716
21. Mazzone E, Pane M, Sormani MP et al (2013) 24 month longitudinal data in ambulant boys with Duchenne Muscular Dystrophy. Plos ONE 8(1):1-6
22. Steffensen B, Hyde S, Lyager S, Mattsson E (2001) Validity of the EK scale: a functional assessment of non-ambulatory individuals with Duchenne muscular dystrophy or spinal muscular atrophy. Physiother Res Int 6(3):119-134
23. Bérard C, Payan C, Hodgkinson I, Fermanian J (2005) MFM Collaborative Study Group. A motor function measure for neuromuscular diseases. Construction and validation study. Neuromuscul Disord 15(7):463-470
24. Mazzone ES, Vasco G, Palermo C, Bianco F, Galluccio C, Ricotti V, Castronovo AD, Mauro MS, Pane M, Mayhew A, Mercuri E (2012) A critical review of functional assessment tools for upper limbs in Duchenne muscular dystrophy. Dev Med Child Neurol 54(10):879-885
25. Phillips MF, Quinlivan RC, Edwards RH, Calverley PM (2001) Changes in spirometry over time as a prognostic marker in patients with Duchenne muscular dystrophy. Am J Respir Crit Care Med 164(12):2191-2194
26. Davis SE, Hynan LS, Limbers CA, Andersen CM, Greene MC, Varni JW, Iannaccone ST (2010) The PedsQL in pediatric patients with Duchenne muscular dystrophy: feasibility, reliability, and validity of the pediatric quality of life inventory neuromuscular module and generic core scales. J Clin Neuromuscul Dis 11(3):97-109
27. Abdel-Salam E, Abdel-Meguid I, Korraa SS (2009) Markers of degeneration and regeneration in Duchenne muscular dystrophy. Acta Myol 28(3):94-100
28. Cárdenas C, Juretić N, Bevilacqua JA, García IE, Figueroa R, Hartley R, Taratuto AL, Gejman R, Riveros N, Molgó J, Jaimovich E (2010) Abnormal distribution of inositol 1,4,5-trisphosphate receptors in human muscle can be related to altered calcium signals and gene expression in Duchenne dystrophy-derived cells. FASEB J 24(9):3210-3221
29. Flanigan KM, Ceco E, Lamar KM, Kaminoh Y, Dunn DM, Mendell JR, King WM, Pestronk A, Florence JM, Mathews KD, Finkel RS, Swoboda KJ, Gappmaier E, Howard MT, Day JW, McDonald C, McNally EM, Weiss RB, United Dystrophinopathy Project (2012) LTBP4 genotype predicts age of ambulatory loss in duchenne muscular dystrophy. Ann Neurol (epub ahead of print)
30. Griffin JL, Des Rosiers C (2009) Applications of metabolomics and proteomics to the mdx mouse model of Duchenne muscular dystrophy: lessons from downstream of the transcriptome. Genome Med 1(3):32
31. Lewis C, Doran P, Ohlendieck K (2012) Proteomic analysis of dystrophic muscle. Methods Mol Biol 798:357-369
32. Rayavarapu S, Coley W, Cakir E, Jahnke V, Takeda S, Aoki Y, Gordish-Dressman H, Jaiswal JK, Hoffman EP, Brown KJ, Hathout Y, Nagaraju K (2013) Identification of disease specific pathways using in vivo SILAC proteomics in dystrophin deficient mdx mouse. Mol Cell Proteomics 12:1061-1073
33. De Paepe B, Creus KK, Martin JJ, De Bleecker JL (2012) Upregulation of chemokines and their receptors in Duchenne muscular dystrophy: potential for attenuation of myofiber necrosis. Muscle Nerve 46(6):917-925
34. Mizuno H, Nakamura A, Aoki Y, Ito N, Kishi S, Yamamoto K, Sekiguchi M, Takeda S, Hashido K (2011) Identification of muscle-specific microRNAs in serum of muscular dystrophy animal models: promising novel blood-based markers for muscular dystrophy. PLoS ONE 6(3):e18388
35. Roberts TC, Blomberg KE, McClorey G, Andaloussi SE, Godfrey C, Betts C, Coursindel T, Gait MJ, Edvard Smith C, Wood MJ (2012) Expression analysis in multiple muscle groups and serum reveals complexity in the MicroRNA transcriptome of the mdx mouse with implications for therapy. Mol Ther Nucleic Acids 1:e39
36. Wang L, Zhou L, Jiang P, Lu L, Chen X, Lan H, Guttridge DC, Sun H, Wang H (2012) Loss of miR-29 in myoblasts contributes to dystrophic muscle pathogenesis. Mol Ther 20(6):1222-1233
37. Cacchiarelli D, Legnini I, Martone J, Cazzella V, D'Amico A, Bertini E, Bozzoni I (2011) miRNAs as serum biomarkers for Duchenne muscular dystrophy. EMBO Mol Med 3(5):258-265
38. Lu QL, Morris GE, Wilton SD, Ly T, Artem'yeva OV, Strong P, Partridge TA (2000) Massive idiosyncratic exon skipping corrects the nonsense mutation in dystrophic mouse muscle and produces functional revertant fibers by clonal expansion. J Cell Biol 148(5):985-996
39. Li D, Shin JH, Duan D (2011) iNOS ablation does not improve specific force of the extensor digitorum longus muscle in dystrophin-deficient mdx4cv mice. PLoS ONE 6(6):e21618
40. Anthony K, Cirak S, Torelli S, Tasca G, Feng L, Arechavala-Gomeza V, Armaroli A, Guglieri M, Straathof CS, Verschuuren JJ, Aartsma-Rus A, Helderman-van den Enden P, Bushby K, Straub V, Sewry C, Ferlini A, Ricci E, Morgan JE, Muntoni F (2011) Dystrophin quantification and clinical correlations in Becker muscular dystrophy: implications for clinical trials. Brain 134(Pt 12):3547-3559
41. Kinali M, Arechavala-Gomeza V, Cirak S, Glover A, Guglieri M, Feng L, Hollingsworth KG, Hunt D, Jungbluth H, Roper HP, Quinlivan RM, Gosalakkal JA, Jayawant S, Nadeau A, Hughes-Carre L, Manzur AY, Mercuri E, Morgan JE, Straub V, Bushby K, Sewry C, Rutherford M, Muntoni F (2011) Muscle histology vs MRI in Duchenne muscular dystrophy. Neurology 76(4):346-353
42. Barton-Davis ER, Cordier L, Shoturma DI, Leland SE, Sweeney HL (1999) Aminoglycoside antibiotics restore dystrophin function to skeletal muscles of mdx mice. J Clin Invest 104(4):375-381
43. Malik V, Rodino-Klapac LR, Viollet L, Wall C, King W, Al-Dahhak R, Lewis S, Shilling CJ, Kota J, Serrano-Munuera C, Hayes J, Mahan JD, Campbell KJ, Banwell B, Dasouki M, Watts V, Sivakumar K, Bien-Willner R, Flanigan KM, Sahenk Z, Barohn RJ, Walker CM, Mendell JR (2010) Gentamicin-induced readthrough of stop codons in Duchenne muscular dystrophy. Ann Neurol 67(6):771-780
44. Welch EM, Barton ER, Zhuo J, Tomizawa Y, Friesen WJ, Trifillis P, Paushkin S, Patel M, Trotta CR, Hwang S, Wilde RG, Karp G, Takasugi J, Chen G, Jones S, Ren H, Moon YC, Corson D, Turpoff AA, Campbell JA, Conn MM, Khan A, Almstead NG, Hedrick J, Mollin A, Risher N, Weetall M, Yeh S, Branstrom AA, Colacino JM, Babiak J, Ju WD, Hirawat S, Northcutt VJ, Miller LL, Spatrick P, He F, Kawana M, Feng H, Jacobson A, Peltz SW, Sweeney HL (2007) PTC124 targets genetic disorders caused by nonsense mutations. Nature 447(7140):87-91
45. Finkel R, Wong B, Bushby K, Reha A, Elfring GL, Miller LL, Babiak J, Morsy MA, Peltz S, Welch E, Atkinson L (2010) Results of a Phase 2b, dose-ranging study of ataluren (PTC124) in nonsense mutation Duchenne/Becker muscular dystrophy. Neuromuscul Disord 20(9-10):657
46. Finkel R, Wong B, Bushby K, Voit T, Morsy M, Elfring GL, Barth J, Peltz SW (2011) The relationship of ataluren plasma concentration and response across clinical studies in nonsense mutation dystrophinopathy. Neuromuscul Disord 21(9-10):707
47. Mendell Jerry R, Katherine Campbell BS et al (2010) Dystrophin immunity in duchenne's muscular dystrophy. N Engl J Med 363(15):1429-1437
48. Muntoni F, Wells D (2007) Genetic treatments in muscular dystrophies. Curr Opin Neurol 20(5):590-594
49. Helderman-van den Enden AT, Straathof CS, Aartsma-Rus A, den Dunnen JT, Verbist BM, Bakker E, Verschuuren JJ, Ginjaar HB (2010) Becker muscular dystrophy patients with deletions around exon 51; a promising outlook for exon skipping therapy in Duchenne patients. Neuromuscul Disord 20(4):251-254
50. Dias N, Stein CA (2002) Antisense oligonucleotides: basic concepts and mechanisms. Mol Cancer Ther 1(5):347-355
51. Heemskerk HA, de Winter CL, de Kimpe SJ, van Kuik-Romeijn P, Heuvelmans N, Platenburg GJ, van Ommen GJ, van Deutekom JC, Aartsma-Rus (2009) In vivo comparison of 2′-O-methyl phosphorothioate and morpholino antisense oligonucleotides for Duchenne muscular dystrophy exon skipping. J Gene Med 11(3):257-266
52. Partridge TA (2011) Impending therapies for Duchenne muscular dystrophy. Curr Opin Neurol 24(5):415-422
53. Cirak S, Arechavala-Gomeza V, Guglieri M, Feng L, Torelli S, Anthony K, Abbs S, Garralda ME, Bourke J, Wells DJ, Dickson G, Wood MJ, Wilton SD, Straub V, Kole R, Shrewsbury SB, Sewry C, Morgan JE, Bushby K, Muntoni F (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 378:595-605
54. Aartsma-Rus A, Janson AA, Kaman WE, Bremmer-Bout M, van Ommen GJ, den Dunnen JT, van Deutekom JC (2004) Antisense-induced multiexon skipping for Duchenne muscular dystrophy makes more sense. Am J Hum Genet 74(1):83-92
55. Adkin CF, Meloni PL, Fletcher S, Adams AM, Muntoni F, Wong B, Wilton SD (2012) Multiple exon skipping strategies to by-pass dystrophin mutations. Neuromuscul Disord 22(4):297-305. doi: 10.1016/j.nmd.2011.10.007
56. Aoki Y, Yokota T, Nagata T, Nakamura A, Tanihata J, Saito T, Duguez SM, Nagaraju K, Hoffman EP, Partridge T, Takeda S (2012) Bodywide skipping of exons 45-55 in dystrophic mdx52 mice by systemic antisense delivery. Proc Natl Acad Sci USA 109(34):13763-13768
57. Yokota T, Nakamura A, Nagata T, Saito T, Kobayashi M, Aoki Y, Echigoya Y, Partridge T, Hoffman EP, Takeda S (2012) Extensive and prolonged restoration of dystrophin expression with vivo-morpholino-mediated multiple exon skipping in dystrophic dogs. Nucleic Acid Ther 22(5):306-315
58. Heemskerk H, de Winter C, van Kuik P, Heuvelmans N, Sabatelli P, Rimessi P, Braghetta P, van Ommen GJ, de Kimpe S, Ferlini A, Aartsma-Rus A, van Deutekom JC (2010) Preclinical PK and PD studies on 2′-O-methyl-phosphorothioate RNA antisense oligonucleotides in the mdx mouse model. Mol Ther 18(6):1210-1217
59. Van Deutekom JC, Janson AA, Ginjaar IB, Frankhuizen WS, Aartsma-Rus A, Bremmer-Bout M, den Dunnen JT, Koop K, Vander Kooi AJ, Goemans NM, de Kimpe SJ, Ekhart PF, Venneker EH, Platenburg GJ, Verschuuren JJ, van Ommen GJ (2007) Local dystrophin restoration with antisense oligonucleotide PRO051. N Engl J Med 357(26):2677-2686
60. Goemans NM, Tulinius M, van den Akker JT, Burm BE, Ekhart PF, Heuvelmans N, Holling T, Janson AA, Platenburg GJ, Sipkens JA, Sitsen JM, Aartsma-Rus A, van Ommen GJ, Buyse G, Darin N, Verschuuren JJ, Campion GV, de Kimpe SJ, van Deutekom JC (2011) Systemic administration of PRO051 in Duchenne's muscular dystrophy. N Engl J Med 364(16):1513-1522
61. Gebski BL, Mann CJ, Fletcher S, Wilton SD (2003) Morpholino antisense oligonucleotide induced dystrophin exon 23 skipping in mdx mouse muscle. Hum Mol Genet 12(15):1801-1811
62. Doran P, Wilton SD, Fletcher S, Ohlendieck K (2009) Proteomic profiling of antisense-induced exon skipping reveals reversal of pathobiochemical abnormalities in dystrophic mdx diaphragm. Proteomics 9(3):671-685
63. 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(6):667-676
64. Aoki Y, Nakamura A, Yokota T, Saito T, Okazawa H, Nagata T, Takeda S (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
65. Kinali M, Arechavala-Gomeza V, Feng L, Cirak S, Hunt D, Adkin C, Guglieri M, Ashton E, Abbs S, Nihoyannopoulos P, Garralda ME, Rutherford M, McCulley C, Popplewell L, Graham IR, Dickson G, Wood MJ, Wells DJ, Wilton SD, Kole R, Straub V, Bushby K, Sewry C, Morgan JE, Muntoni F (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(10):918-928
66. Anthony K, Feng L, Arechavala-Gomeza V, Guglieri M, Straub V, Bushby K, Cirak S, Morgan J, Muntoni F (2012) Exon skipping quantification by qRT-PCR in Duchenne muscular dystrophy patients treated with the antisense oligomer eteplirsen. Hum Gene Ther Methods 23:336-345
67. Yin H, Moulton HM, Seow Y, Boyd C, Boutilier J, Iverson P, Wood MJ (2008) Cell-penetrating peptide-conjugated antisense oligonucleotides restore systemic muscle and cardiac dystrophin expression and function. Hum Mol Genet 17(24):3909-3918
68. Moulton HM, Moulton JD (2010) Morpholinos and their peptide conjugates: therapeutic promise and challenge for Duchenne muscular dystrophy. Biochim Biophys Acta 1798(12):2296-2303
69. Nishida Atsushi, Kataoka Naoyuki, Takeshima Yasuhiro, Yagi Mariko, Awano Hiroyuki, Ota Mitsunori, Itoh Kyoko, Hagiwara Masatoshi, Matsuo Masafumi (2011) Chemical treatment enhances skipping of a mutated exon in the dystrophin gene. Nat Commun 2:308
70. Hu Y, Wu B, Zillmer A, Lu P, Benrashid E, Wang M, Doran T, Shaban M, Wu X, Lu QL (2010) Guanine analogues enhance antisense oligonucleotide-induced exon skipping in dystrophin gene in vitro and in vivo. Mol Ther 18(4):812-818
71. Verhaart IE, Aartsma-Rus A (2012). The effect of 6-thioguanine on alternative splicing and antisense-mediated exon skipping treatment for duchenne muscular dystrophy. PLoS Curr 4
72. Kendall GC, Mokhonova EI, Moran M, Sejbuk NE, Wang DW, Silva O, Wang RT, Martinez L, Lu QL, Damoiseaux R, Spencer MJ, Nelson SF, Miceli MC (2012) Dantrolene enhances antisense-mediated exon skipping in human and mouse models of duchenne muscular dystrophy. Sci Transl Med 4(164)
73. Dabertrand F, Mironneau J, Henaff M, Macrez N, Morel JL (2010) Comparison between gentamycin and exon skipping treatments to restore ryanodine receptor subtype 2 functions in mdx mouse duodenum myocytes. Eur J Pharmacol 628(1-3):36-41
74. Pichavant C, Aartsma-Rus A, Clemens PR, Davies KE, Dickson G, Takeda S, Wilton SD, Wolff JA, Wooddell CI, Xiao X, Tremblay JP (2011) Current status of pharmaceutical and genetic therapeutic approaches to treat DMD. Mol Ther 19(5):830-840
75. Kobinger GP, Louboutin JP, Barton ER, Sweeney HL, Wilson JM (2003) Correction of the dystrophic phenotype by in vivo targeting of muscle progenitor cells. Hum Gene Ther 14(15):1441-1449
76. Benchaouir R, Meregalli M, Farini A, D'Antona G, Belicchi M, Goyenvalle A, Battistelli M, Bresolin N, Bottinelli R, Garcia L, Torrente Y (2007) Restoration of human dystrophin following transplantation of exon-skipping-engineered DMD patient stem cells into dystrophic mice. Cell Stem Cell 1(6):646-657
77. Athanasopoulos T, Foster H, Foster K, Dickson G (2011) Codon optimization of the microdystrophin gene for Duchene muscular dystrophy gene therapy. Methods Mol Biol 709:21-37
78. Wang B, Li J, Qiao C, Chen C, Hu P, Zhu X, Zhou L, Bogan J, Kornegay J, Xiao X (2008) A canine minidystrophin is functional and therapeutic in mdx mice. Gene Ther 15(15):1099-1106
79. Liu N, Williams AH, Maxeiner JM, Bezprozvannaya S, Shelton JM, Richardson JA, Bassel-Duby R, Olson EN (2012) microRNA-206 promotes skeletal muscle regeneration and delays progression of Duchenne muscular dystrophy in mice. Clin Invest 122(6):2054-2065
80. Wang L, Zhou L, Jiang P, Lu L, Chen X, Lan H, Guttridge DC, Sun H, Wang H (2012) Loss of miR-29 in myoblasts contributes to dystrophic muscle pathogenesis. Mol Ther 20(6):1222-1233
81. Biggar WD, Harris VA, Eliasoph L, Alman B (2006) Long-term benefits of deflazacort treatment for boys with Duchenne muscular dystrophy in their second decade. Neuromuscul Disord 16(4):249-255
82. Fairclough RJ, Perkins KJ, Davies KE (2012) Pharmacologically targeting the primary defect and downstream pathology in Duchenne muscular dystrophy. Curr Gene Ther 12(3):206-244
83. Manzur AY, Kuntzer T, Pike M, Swan A (2004) Glucocorticoid corticosteroids for Duchenne muscular dystrophy. Cochrane Database Syst Rev (2):CD003725
84. Kirschner J (2010) Treatment of Duchenne muscular dystrophy with ciclosporin A: a randomised, double-blind, placebo-controlled multicentre trial. Lancet Neurol 9(11):1053-1059
85. Consalvi S, Saccone V, Giordani L, Minetti G, Mozzetta C, Puri PL (2011) Histone deacetylase inhibitors in the treatment of muscular dystrophies: epigenetic drugs for genetic diseases. Mol Med 17(5-6):457-465
86. Iezzi S, Cossu G, Nervi C, Sartorelli V, Puri PL (2002) Stage-specific modulation of skeletal myogenesis by inhibitors of nuclear deacetylases. Proc Natl Acad Sci USA 99(11):7757-7762
87. Iezzi S, Di Padova M, Serra C, Caretti G, Simone C, Maklan E, Minetti G, Zhao P, Hoffman EP, Puri PL, Sartorelli V (2004) Deacetylase inhibitors increase muscle cell size by promoting myoblast recruitment and fusion through induction of follistatin. Dev Cell 6(5):673-684
88. Bredt DS, Snyder SH (1990) Isolation of nitric oxide synthetase, a calmodulin-requiring enzyme. Proc Natl Acad Sci USA 87:682-685
89. Sander M, Chavoshan B, Harris SA, Iannaccone ST, Stull JT, Thomas GD, Victor RG (2000) Functional muscle ischemia in neuronal nitric oxide synthase-deficient skeletal muscle of children with Duchenne muscular dystrophy. Proc Natl Acad Sci USA 97(25):13818-13823
90. Buono R, Vantaggiato C, Pisa V, Azzoni E, Bassi MT, Brunelli S, Sciorati C, Clementi E (2012) Nitric oxide sustains long-term skeletal muscle regeneration by regulating fate of satellite cells via signaling pathways requiring Vangl2 and cyclic GMP. Stem Cells 30(2):197-209
91. Sciorati C, Miglietta D, Buono R, Pisa V, Cattaneo D, Azzoni E, Brunelli S, Clementi E (2011) A dual acting compound releasing nitric oxide (NO) and ibuprofen, NCX 320, shows significant therapeutic effects in a mouse model of muscular dystrophy. Pharmacol Res 64(3):210-217
92. D'Angelo MG, Gandossini S, Martinelli Boneschi F, Sciorati C, Bonato S, Brighina E, Comi GP, Turconi AC, Magri F, Stefanoni G, Brunelli S, Bresolin N, Cattaneo D, Clementi E (2012) Nitric oxide donor and non steroidal anti inflammatory drugs as a therapy for muscular dystrophies: evidence from a safety study with pilot efficacy measures in adult dystrophic patients. Pharmacol Res 65(4):472-479
93. Bella AJ, Deyoung LX, Al-Numi M, Brock GB (2007) Daily administration of phosphodiesterase type 5 inhibitors for urological and non urological indications. Eur Urol 52(4):990-1005
94. Asai A, Sahani N, Kaneki M, Ouchi Y, Martyn JA, Yasuhara SE (2007) Primary role of functional ischemia, quantitative evidence for the two-hit mechanism, and phosphodiesterase-5 inhibitor therapy in mouse muscular dystrophy. PLoS ONE 2(8):e806
95. Martin EA, Barresi R, Byrne BJ, Tsimerinov EI, Scott BL, Walker AE, Gurudevan SV, Anene F, Elashoff RM, Thomas GD, Victor RG (2012) Tadalafil alleviates muscle ischemia in patients with becker muscular dystrophy. Sci Transl Med 4(162):162ra155
96. Buyse GM, Van der Mieren G, Erb M, D'hooge J, Herijgers P, Verbeken E, Jara A, Van Den Bergh A, Mertens L, Courdier-Fruh I, Barzaghi P, Meier T (2009) Long-term blinded placebo-controlled study of SNT-MC17/idebenone in the dystrophin deficient mdx mouse: cardiac protection and improved exercise performance. Eur Heart J 30(1):116-124
97. Buyse GM, Goemans N, van den Hauwe M, Thijs D, de Groot IJ, Schara U, Ceulemans B, Meier T, Mertens L (2011) Idebenone as a novel, therapeutic approach for DMD: results from a 12 month, double-blind, randomized placebo-controlled trial. Neuromuscul Disord 21(6):396-405
98. Clemmons DR (2009) Role of IGF-I in skeletal muscle mass maintenance. Trends Endocrinol Metab 20(7):349-356
99. Lynch GS, Cuffe SA, Plant DR, Gregorevic P (2001) IGF-I treatment improves the functional properties of fast- and slow-twitch skeletal muscles from dystrophic mice. Neuromuscul Disord 11(3):260-268
100. Palmieri B, Tremblay JP, Daniele L (2010) Past, present and future of myoblast transplantation in the treatment of Duchenne muscular dystrophy. Pediatr Transpl 14(7):813-819
101. Tedesco FS, Hoshiya H, D'Antona G, Gerli MF, Messina G, Antonini S, Tonlorenzi R, Benedetti S, Berghella L, Torrente Y, Kazuki Y, Bottinelli R, Oshimura M, Cossu G (2011) Stem cell-mediated transfer of a human artificial chromosome ameliorates muscular dystrophy. Sci Transl Med 3(96):96ra78
102. Díaz-Manera J, Touvier T, Dellavalle A, Tonlorenzi R, Tedesco FS, Messina G, Meregalli M, Navarro C, Perani L, Bonfanti C, Illa I, Torrente Y, Cossu G (2010) Partial dysferlin reconstitution by adult murine mesoangioblasts is sufficient for full functional recovery in a murine model of dysferlinopathy. Cell Death Dis 1(8):e61
103. Belicchi M, Pisati F, Lopa R, Porretti L, Fortunato F, Sironi M, Scalamogna M, Parati EA, Bresolin N, Torrente Y (2004) Human skin-derived stem cells migrate throughout forebrain and differentiate into astrocytes after injection into adult mouse brain. J Neurosci Res 77(4):475-486
104. Torrente Y, Belicchi M, Marchesi C et al (2007) Autologous transplantation of muscle-derived CD133+ stem cells in Duchenne muscle patients. Cell Transpl 16(6):563-577