Research progress of Duchenne muscular dystrophy_West China Medical Journal

Authors：

LIU Zhaofei ,  XIAO Xingjun

Department of Neurology, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150081, P. R. China;

Corresponding author：

XIAO Xingjun, Email: xxiao@hrbmu.edu.cn

Keywords：

Duchenne muscular dystrophy; Dystrophin protein; Gene therapy; Exon skipping; Stem cell theraphy

DOI：

10.7507/1002-0179.202002427

Video：

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Duchenne muscular dystrophy is an X-linked inherited progressive degenerative muscle disease caused by mutations in the dystrophin gene, and is one of the most common progressive muscular dystrophies. We will review the selection of genetic diagnosis methods for Duchenne muscular dystrophy, the selection of experimental animal models, and treatment for the primary cause (including gene replacement therapy, exon skipping therapy, genome editing, stop codon read-through therapy, and stem cell therapy), the treatment of secondary pathological reactions and methods of assessing disease progression. The purpose is to enrich clinicians’ knowledge of the disease and provide a reference and help for the clinical diagnosis and treatment of Duchenne muscular dystrophy.

Citation： LIU Zhaofei, XIAO Xingjun. Research progress of Duchenne muscular dystrophy. West China Medical Journal, 2020, 35(7): 873-877. doi: 10.7507/1002-0179.202002427 Copy

1.	Ryder S, Leadley RM, Armstrong N, et al. The burden, epidemiology, costs and treatment for Duchenne muscular dystrophy: an evidence review. Orphanet J Rare Dis, 2017, 12(1): 79.
2.	Okubo M, Minami N, Goto K, et al. Genetic diagnosis of Duchenne/Becker muscular dystrophyusing next-generation sequencing: validation analysis of DMD mutations. J Hum Genet, 2016, 61(6): 483-489.
3.	ansović I, Barišić I, Dumić K. Improved detection of deletions and duplications in the DMD gene using the multiplex ligation-dependent probe amplification (MLPA) method. Biochem Genet, 2013, 51(3/4): 189-201.
4.	Ankala A, da Silva C, Gualandi F, et al. A comprehensive genomic approach for neuromuscular diseases gives a high diagnostic yield. Ann Neurol, 2015, 77(2): 206-214.
5.	Chamberlain JS, Metzger J, Reyes M, et al. Dystrophin-deficient mdx mice display a reduced life span and are susceptible to spontaneous rhabdomyosarcoma. FASEB J, 2007, 21(9): 2195-2204.
6.	McGreevy JW, Hakim CH, McIntosh MA, et al. Animal models of Duchenne muscular dystrophy: from basic mechanisms to gene therapy. Dis Model Mech, 2015, 8(3): 195-213.
7.	Duan D. Systemic AAV micro-dystrophin gene therapy for Duchenne muscular dystrophy. Mol Ther, 2018, 26(10): 2337-2356.
8.	Leborgne C, Latournerie V, Boutin S, et al. Prevalence and long-term monitoring of humoral immunity against adeno-associated virus in Duchenne muscular dystrophy patients. Cell Immunol, 2019, 342: 103780.
9.	Niks EH, Aartsma-Rus A. Exon skipping: a first in class strategy for Duchenne muscular dystrophy. Expert Opin Biol Ther, 2017, 17(2): 225-236.
10.	Echigoya Y, Lim KRQ, Nakamura A, et al. Multiple exon skipping in the Duchenne muscular dystrophy hot spots: prospects and challenges. J Pers Med, 2018, 8(4): 41.
11.	Bladen CL, Salgado D, Monges S, et al. The TREAT-NMD DMD global database: analysis of more than 7, 000 Duchenne muscular dystrophy mutations. Hum Mutat, 2015, 36(4): 395-402.
12.	Aartsma-Rus A, Krieg AM. FDA approves eteplirsen for Duchenne muscular dystrophy: the next chapter in the eteplirsen saga. Nucleic Acid Ther, 2017, 27(1): 1-3.
13.	Charleston JS, Schnell FJ, Dworzak J, et al. Eteplirsen treatment for Duchenne muscular dystrophy: exon skipping and dystrophin production. Neurology, 2018, 90(24): e2146-e2154.
14.	Goemans N, Mercuri E, Belousova E, et al. A randomized placebo-controlled phase 3 trial of an antisense oligonucleotide, drisapersen, in Duchenne muscular dystrophy. Neuromuscul Disord, 2018, 28(1): 4-15.
15.	Lim KRQ, Yoon C, Yokota T. Applications of CRISPR/Cas9 for the treatment of Duchenne muscular dystrophy. J Pers Med, 2018, 8(4): 38.
16.	Bengtsson NE, Hall JK, Odom GL, et al. Muscle-specific CRISPR/Cas9 dystrophin gene editing ameliorates pathophysiology in a mouse model for Duchenne muscular dystrophy. Nat Commun, 2017, 8: 14454.
17.	Long C, Amoasii L, Mireault AA, et al. Postnatal genome editing partially restores dystrophin expression in a mouse model of muscular dystrophy. Science, 2016, 351(6271): 400-403.
18.	Hakim CH, Wasala NB, Nelson CE, et al. AAV CRISPR editing rescues cardiac and muscle function for 18 months in dystrophic mice. JCI insight, 2018, 3(23): e124297.
19.	Nelson CE, Wu Y, Gemberling MP, et al. Long-term evaluation of AAV-CRISPR genome editing for Duchenne muscular dystrophy. Nat Med, 2019, 25(3): 427-432.
20.	Kemaladewi DU, Cohn RD. Exon snipping in Duchenne muscular dystrophy. Trends Mol Med, 2016, 22(3): 187-189.
21.	El Refaey M, Xu L, Gao Y, et al. In vivo genome editing restores dystrophin expression and cardiac function in dystrophic mice. Circ Res, 2017, 121(8): 923-929.
22.	Maggio I, Liu J, Janssen JM, et al. Adenoviral vectors encoding CRISPR/Cas9 multiplexes rescue dystrophin synthesis in unselected populations of DMD muscle cells. Sci Rep, 2016, 6: 37051.
23.	Arnett AL, Konieczny P, Ramos JN, et al. Adeno-associated viral (AAV) vectors do not efficiently target muscle satellite cells. Mol Ther Methods Clin Dev, 2014, 1: 14038.
24.	Aartsma-Rus A, Ginjaar IB, Bushby K. The importance of genetic diagnosis for Duchenne muscular dystrophy. J Med Genet, 2016, 53(3): 145-151.
25.	Karijolich J, Yu YT. Therapeutic suppression of premature termination codons: mechanisms and clinical considerations (review). Int J Mol Med, 2014, 34(2): 355-362.
26.	Welch EM, Barton ER, Zhuo J, et al. PTC124 targets genetic disorders caused by nonsense mutations. Nature, 2007, 447(7140): 87-91.
27.	McDonald CM, Campbell C, Torricelli RE, et al. Ataluren in patients with nonsense mutation Duchenne muscular dystrophy (ACT DMD): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet, 2017, 390(10101): 1489-1498.
28.	Skuk D, Tremblay JP. Cell therapy in muscular dystrophies: many promises in mice and dogs, few facts in patients. Expert Opin Biol Ther, 2015, 15(9): 1307-1319.
29.	Young CS, Hicks MR, Ermolova NV, et al. A single CRISPR-Cas9 deletion strategy that targets the majority of DMD patients restores dystrophin function in hiPSC-derived muscle cells. Cell Stem Cell, 2016, 18(4): 533-540.
30.	Cossu G, Previtali SC, Napolitano S, et al. Intra-arterial transplantation of HLA-matched donor mesoangioblasts in Duchenne muscular dystrophy. EMBO Mol Med, 2016, 8(12): 1470-1471.
31.	Kennedy TL, Guiraud S, Edwards B, et al. Micro-utrophin improves cardiac and skeletal muscle function of severely affected D2/mdx mice. Mol Ther Methods Clin Dev, 2018, 11: 92-105.
32.	Shin J, Tajrishi MM, Ogura Y, et al. Wasting mechanisms in muscular dystrophy. Int J Biochem Cell Biol, 2013, 45(10): 2266-2279.
33.	McDonald CM, Henricson EK, Abresch RT, et al. Long-term effects of glucocorticoids on function, quality of life, and survival in patients with Duchenne muscular dystrophy: a prospective cohort study. Lancet, 2018, 391(10119): 451-461.
34.	Newton R, Holden NS. Separating transrepression and transactivation: a distressing divorce for the glucocorticoid receptor?. Mol Pharmacol, 2007, 72(4): 799-809.
35.	Yoon SH, Grynpas MD, Mitchell J. Growth hormone increases bone toughness and decreases muscle inflammation in glucocorticoid-treated mdx mice, model of Duchenne muscular dystrophy. J Bone Miner Res, 2019, 34(8): 1473-1486.
36.	Baudy AR, Reeves EK, Damsker JM, et al. Δ-9, 11 modification of glucocorticoids dissociates nuclear factor-κB inhibitory efficacy from glucocorticoid response element-associated side effects. J Pharmacol Exp Ther, 2012, 343(1): 225-232.
37.	Hoffman EP, Riddle V, Siegler MA, et al. Phase 1 trial of vamorolone, a first-in-class steroid, shows improvements in side effects via biomarkers bridged to clinical outcomes. Steroids, 2018, 134: 43-52.
38.	Hoffman EP, Schwartz BD, Mengle-Gaw LJ, et al. Vamorolone trial in Duchenne muscular dystrophy shows dose-related improvement of muscle function. Neurology, 2019, 93(13): e1312-e1323.
39.	Signorelli M, Ayoglu B, Johansson C, et al. Longitudinal serum biomarker screening identifies malate dehydrogenase 2 as candidate prognostic biomarker for Duchenne muscular dystrophy. J Cachexia Sarcopenia Muscle, 2020, 11(2): 505-517.
40.	Chrzanowski SM, Darras BT, Rutkove SB. The value of imaging and composition-based biomarkers in Duchenne muscular dystrophy clinical trials. Neurotherapeutics, 2020, 17(1): 142-152.
41.	Leitner ML, Kapur K, Darras BT, et al. Electrical impedance myography for reducing sample size in Duchenne muscular dystrophy trials. Ann Clin Transl Neurol, 2020, 7(1): 4-14.
42.	Regensburger AP, Fonteyne LM, Jüngert J, et al. Detection of collagens by multispectral optoacoustic tomography as an imaging biomarker for Duchenne muscular dystrophy. Nat Med, 2019, 25(12): 1905-1915.
43.	Barnard AM, Willcocks RJ, Triplett WT, et al. MR biomarkers predict clinical function in Duchenne muscular dystrophy. Neurology, 2020, 94(9): e897-e909.

1. Ryder S, Leadley RM, Armstrong N, et al. The burden, epidemiology, costs and treatment for Duchenne muscular dystrophy: an evidence review. Orphanet J Rare Dis, 2017, 12(1): 79.
2. Okubo M, Minami N, Goto K, et al. Genetic diagnosis of Duchenne/Becker muscular dystrophyusing next-generation sequencing: validation analysis of DMD mutations. J Hum Genet, 2016, 61(6): 483-489.
3. ansović I, Barišić I, Dumić K. Improved detection of deletions and duplications in the DMD gene using the multiplex ligation-dependent probe amplification (MLPA) method. Biochem Genet, 2013, 51(3/4): 189-201.
4. Ankala A, da Silva C, Gualandi F, et al. A comprehensive genomic approach for neuromuscular diseases gives a high diagnostic yield. Ann Neurol, 2015, 77(2): 206-214.
5. Chamberlain JS, Metzger J, Reyes M, et al. Dystrophin-deficient mdx mice display a reduced life span and are susceptible to spontaneous rhabdomyosarcoma. FASEB J, 2007, 21(9): 2195-2204.
6. McGreevy JW, Hakim CH, McIntosh MA, et al. Animal models of Duchenne muscular dystrophy: from basic mechanisms to gene therapy. Dis Model Mech, 2015, 8(3): 195-213.
7. Duan D. Systemic AAV micro-dystrophin gene therapy for Duchenne muscular dystrophy. Mol Ther, 2018, 26(10): 2337-2356.
8. Leborgne C, Latournerie V, Boutin S, et al. Prevalence and long-term monitoring of humoral immunity against adeno-associated virus in Duchenne muscular dystrophy patients. Cell Immunol, 2019, 342: 103780.
9. Niks EH, Aartsma-Rus A. Exon skipping: a first in class strategy for Duchenne muscular dystrophy. Expert Opin Biol Ther, 2017, 17(2): 225-236.
10. Echigoya Y, Lim KRQ, Nakamura A, et al. Multiple exon skipping in the Duchenne muscular dystrophy hot spots: prospects and challenges. J Pers Med, 2018, 8(4): 41.
11. Bladen CL, Salgado D, Monges S, et al. The TREAT-NMD DMD global database: analysis of more than 7, 000 Duchenne muscular dystrophy mutations. Hum Mutat, 2015, 36(4): 395-402.
12. Aartsma-Rus A, Krieg AM. FDA approves eteplirsen for Duchenne muscular dystrophy: the next chapter in the eteplirsen saga. Nucleic Acid Ther, 2017, 27(1): 1-3.
13. Charleston JS, Schnell FJ, Dworzak J, et al. Eteplirsen treatment for Duchenne muscular dystrophy: exon skipping and dystrophin production. Neurology, 2018, 90(24): e2146-e2154.
14. Goemans N, Mercuri E, Belousova E, et al. A randomized placebo-controlled phase 3 trial of an antisense oligonucleotide, drisapersen, in Duchenne muscular dystrophy. Neuromuscul Disord, 2018, 28(1): 4-15.
15. Lim KRQ, Yoon C, Yokota T. Applications of CRISPR/Cas9 for the treatment of Duchenne muscular dystrophy. J Pers Med, 2018, 8(4): 38.
16. Bengtsson NE, Hall JK, Odom GL, et al. Muscle-specific CRISPR/Cas9 dystrophin gene editing ameliorates pathophysiology in a mouse model for Duchenne muscular dystrophy. Nat Commun, 2017, 8: 14454.
17. Long C, Amoasii L, Mireault AA, et al. Postnatal genome editing partially restores dystrophin expression in a mouse model of muscular dystrophy. Science, 2016, 351(6271): 400-403.
18. Hakim CH, Wasala NB, Nelson CE, et al. AAV CRISPR editing rescues cardiac and muscle function for 18 months in dystrophic mice. JCI insight, 2018, 3(23): e124297.
19. Nelson CE, Wu Y, Gemberling MP, et al. Long-term evaluation of AAV-CRISPR genome editing for Duchenne muscular dystrophy. Nat Med, 2019, 25(3): 427-432.
20. Kemaladewi DU, Cohn RD. Exon snipping in Duchenne muscular dystrophy. Trends Mol Med, 2016, 22(3): 187-189.
21. El Refaey M, Xu L, Gao Y, et al. In vivo genome editing restores dystrophin expression and cardiac function in dystrophic mice. Circ Res, 2017, 121(8): 923-929.
22. Maggio I, Liu J, Janssen JM, et al. Adenoviral vectors encoding CRISPR/Cas9 multiplexes rescue dystrophin synthesis in unselected populations of DMD muscle cells. Sci Rep, 2016, 6: 37051.
23. Arnett AL, Konieczny P, Ramos JN, et al. Adeno-associated viral (AAV) vectors do not efficiently target muscle satellite cells. Mol Ther Methods Clin Dev, 2014, 1: 14038.
24. Aartsma-Rus A, Ginjaar IB, Bushby K. The importance of genetic diagnosis for Duchenne muscular dystrophy. J Med Genet, 2016, 53(3): 145-151.
25. Karijolich J, Yu YT. Therapeutic suppression of premature termination codons: mechanisms and clinical considerations (review). Int J Mol Med, 2014, 34(2): 355-362.
26. Welch EM, Barton ER, Zhuo J, et al. PTC124 targets genetic disorders caused by nonsense mutations. Nature, 2007, 447(7140): 87-91.
27. McDonald CM, Campbell C, Torricelli RE, et al. Ataluren in patients with nonsense mutation Duchenne muscular dystrophy (ACT DMD): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet, 2017, 390(10101): 1489-1498.
28. Skuk D, Tremblay JP. Cell therapy in muscular dystrophies: many promises in mice and dogs, few facts in patients. Expert Opin Biol Ther, 2015, 15(9): 1307-1319.
29. Young CS, Hicks MR, Ermolova NV, et al. A single CRISPR-Cas9 deletion strategy that targets the majority of DMD patients restores dystrophin function in hiPSC-derived muscle cells. Cell Stem Cell, 2016, 18(4): 533-540.
30. Cossu G, Previtali SC, Napolitano S, et al. Intra-arterial transplantation of HLA-matched donor mesoangioblasts in Duchenne muscular dystrophy. EMBO Mol Med, 2016, 8(12): 1470-1471.
31. Kennedy TL, Guiraud S, Edwards B, et al. Micro-utrophin improves cardiac and skeletal muscle function of severely affected D2/mdx mice. Mol Ther Methods Clin Dev, 2018, 11: 92-105.
32. Shin J, Tajrishi MM, Ogura Y, et al. Wasting mechanisms in muscular dystrophy. Int J Biochem Cell Biol, 2013, 45(10): 2266-2279.
33. McDonald CM, Henricson EK, Abresch RT, et al. Long-term effects of glucocorticoids on function, quality of life, and survival in patients with Duchenne muscular dystrophy: a prospective cohort study. Lancet, 2018, 391(10119): 451-461.
34. Newton R, Holden NS. Separating transrepression and transactivation: a distressing divorce for the glucocorticoid receptor?. Mol Pharmacol, 2007, 72(4): 799-809.
35. Yoon SH, Grynpas MD, Mitchell J. Growth hormone increases bone toughness and decreases muscle inflammation in glucocorticoid-treated mdx mice, model of Duchenne muscular dystrophy. J Bone Miner Res, 2019, 34(8): 1473-1486.
36. Baudy AR, Reeves EK, Damsker JM, et al. Δ-9, 11 modification of glucocorticoids dissociates nuclear factor-κB inhibitory efficacy from glucocorticoid response element-associated side effects. J Pharmacol Exp Ther, 2012, 343(1): 225-232.
37. Hoffman EP, Riddle V, Siegler MA, et al. Phase 1 trial of vamorolone, a first-in-class steroid, shows improvements in side effects via biomarkers bridged to clinical outcomes. Steroids, 2018, 134: 43-52.
38. Hoffman EP, Schwartz BD, Mengle-Gaw LJ, et al. Vamorolone trial in Duchenne muscular dystrophy shows dose-related improvement of muscle function. Neurology, 2019, 93(13): e1312-e1323.
39. Signorelli M, Ayoglu B, Johansson C, et al. Longitudinal serum biomarker screening identifies malate dehydrogenase 2 as candidate prognostic biomarker for Duchenne muscular dystrophy. J Cachexia Sarcopenia Muscle, 2020, 11(2): 505-517.
40. Chrzanowski SM, Darras BT, Rutkove SB. The value of imaging and composition-based biomarkers in Duchenne muscular dystrophy clinical trials. Neurotherapeutics, 2020, 17(1): 142-152.
41. Leitner ML, Kapur K, Darras BT, et al. Electrical impedance myography for reducing sample size in Duchenne muscular dystrophy trials. Ann Clin Transl Neurol, 2020, 7(1): 4-14.
42. Regensburger AP, Fonteyne LM, Jüngert J, et al. Detection of collagens by multispectral optoacoustic tomography as an imaging biomarker for Duchenne muscular dystrophy. Nat Med, 2019, 25(12): 1905-1915.
43. Barnard AM, Willcocks RJ, Triplett WT, et al. MR biomarkers predict clinical function in Duchenne muscular dystrophy. Neurology, 2020, 94(9): e897-e909.

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