Abstract
Duchenne muscular dystrophy (DMD) is a fatal X-linked muscle wasting disease. The disease is due to mutations in the DMD gene that encodes for a large intracellular protein called dystrophin. Dystrophin plays a critical role in linking the internal cytoskeleton of the striated muscle cell with the extracellular matrix as well as having cell signalling functions. In its absence muscle contraction is associated with cycles of damage, repair, inflammation and fibrosis with eventual loss of muscle and replacement with fat. Experiments in animal models of DMD have generated a number of different approaches to the induction of dystrophin including viral vector mediated delivery of a recombinant dystrophin gene, antisense oligonucleotide mediated exon-skipping to restore the open reading frame in the dystrophin mRNA, read-through of premature stop mutations, genome modification using CRISPR-Cas9 or cell based transfer of a functional dystrophin gene. In all cases, it will be important to understand how much dystrophin expression is required for a clinically effective therapy and this review examines the data from humans and animal models to estimate the percentage of endogenous dystrophin that is likely to have significant clinical benefit. While there are a number of important caveats to consider, including the appropriate outcome measures, this review suggests that approximately 20% of endogenous levels uniformly distributed within the skeletal muscles and the heart may be sufficient to largely prevent disease progression.
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Aartsma-Rus A, Morgan J, Lonkar P, Neubert H, Owens J, Binks M, Montolio M, Phadke R, Datson N, Van Deutekom J, Morris GE, Rao VA, Hoffman EP, Muntoni F, Arechavala-Gomeza V, workshop participants (2019) Report of a TREAT-NMD/World Duchenne Organisation meeting on dystrophin quantification methodology. J Neuromuscul Dis 6(1):147–159. https://doi.org/10.3233/JND-180357
Alter J, Lou F, Rabinowitz A, Yin H, Rosenfeld J, Wilton SD, Partridge TA, Lu QL (2006) Systemic delivery of morpholino oligonucleotide restores dystrophin expression bodywide and improves dystrophic pathology. Nat Med 12(2):175–177
Amoasii L, Hildyard JCW, Li H, Sanchez-Ortiz E, Mireault A, Caballero D, Harron R, Stathopoulou TR, Massey C, Shelton JM, Bassel-Duby R, Piercy RJ, Olson EN (2018) Gene editing restores dystrophin expression in a canine model of Duchenne muscular dystrophy. Science 362(6410):86–91. https://doi.org/10.1126/science.aau1549
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. https://doi.org/10.1093/brain/awr291
Anthony K, Arechavala-Gomeza V, Taylor LE, Vulin A, Kaminoh Y, Torelli S, Feng L, Janghra N, Bonne G, Beuvin M, Barresi R, Henderson M, Laval S, Lourbakos A, Campion G, Straub V, Voit T, Sewry CA, Morgan JE, Flanigan KM, Muntoni F (2014) Dystrophin quantification: biological and translational research implications. Neurology 83(22):2062–2069. https://doi.org/10.1212/WNL.0000000000001025
Araki E, Nakamura K, Nakao K, Kameya S, Kobayashi O, Nonaka I, Kobayashi T, Katsuki M (1997) Targeted disruption of exon 52 in the mouse dystrophin gene induced muscle degeneration similar to that observed in Duchenne muscular dystrophy. Biochem Biophys Res Commun 238(2):492–497
Azofeifa J, Voit T, Hübner C, Cremer M (1995) X-chromosome methylation in manifesting and healthy carriers of dystrophinopathies: concordance of activation ratios among first degree female relatives and skewed inactivation as cause of the affected phenotypes. Hum Genet 96(2):167–176
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
Beekman C, Janson AA, Baghat A, van Deutekom JC, Datson NA (2018) Use of capillary Western immunoassay (Wes) for quantification of dystrophin levels in skeletal muscle of healthy controls and individuals with Becker and Duchenne muscular dystrophy. PLoS ONE 13(4):e0195850. https://doi.org/10.1371/journal.pone.0195850
Bello L, Flanigan KM, Weiss RB, United Dystrophinopathy Project, Spitali P, Aartsma-Rus A, Muntoni F, Zaharieva I, Ferlini A, Mercuri E, Tuffery-Giraud S, Claustres M, Straub V, Lochmüller H, Barp A, Vianello S, Pegoraro E, Punetha J, Gordish-Dressman H, Giri M, McDonald CM, Hoffman EP, Cooperative International Neuromuscular Research Group (2016) Association study of exon variants in the NF-κB and TGFβ pathways identifies CD40 as a modifier of Duchenne muscular dystrophy. Am J Hum Genet 99(5):1163–1171. https://doi.org/10.1016/j.ajhg.2016.08.023
Betts CA, McClorey G, Healicon R, Hammond SM, Manzano R, Muses S, Ball V, Godfrey C, Merritt TM, van Westering T, O’Donovan L, Wells KE, Gait MJ, Wells DJ, Tyler D, Wood MJ (2019) Cmah-dystrophin deficient mdx mice display an accelerated cardiac phenotype that is improved following peptide-PMO exon skipping treatment. Hum Mol Genet 28(3):396–406. https://doi.org/10.1093/hmg/ddy346
Brown KJ, Marathi R, Fiorillo AA, Ciccimaro EF, Sharma S, Rowlands DS, Rayavarapu S, Nagaraju K, Hoffman EP, Hathout Y (2012) Accurate quantitation of dystrophin protein in human skeletal muscle using mass spectrometry. J Bioanal Biomed 7:001
Bulfield G, Siller WG, Wight PA, Moore KJ (1984) X chromosome-linked muscular dystrophy (mdx) in the mouse. Proc Natl Acad Sci USA 81(4):1189–1192
Chamberlain JS, Metzger J, Reyes M, Townsend D, Faulkner JA (2007) Dystrophin-deficient mdx mice display a reduced life span and are susceptible to spontaneous rhabdomyosarcoma. FASEB J 21(9):2195–2204
Chandrasekharan K, Yoon JH, Xu Y, deVries S, Camboni M, Janssen PM, Varki A, Martin PT (2010) A human-specific deletion in mouse Cmah increases disease severity in the mdx model of Duchenne muscular dystrophy. Sci Transl Med 2(42):42ra54
Chapman VM, Miller DR, Armstrong D, Caskey CT (1989) Recovery of induced mutations for X chromosome-linked muscular dystrophy in mice. Proc Natl Acad Sci USA 86(4):1292–1296
Childers MK, Okamura CS, Bogan DJ, Bogan JR, Petroski GF, McDonald K, Kornegay JN (2002) Eccentric contraction injury in dystrophic canine muscle. Arch Phys Med Rehabil 83(11):1572–1578
Coley WD, Bogdanik L, Vila MC, Yu Q, Van Der Meulen JH, Rayavarapu S, Novak JS, Nearing M, Quinn JL, Saunders A, Dolan C, Andrews W, Lammert C, Austin A, Partridge TA, Cox GA, Lutz C, Nagaraju K (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
Cooper BJ, Winand NJ, Stedman H, Valentine BA, Hoffman EP, Kunkel LM, Scott MO, Fischbeck KH, Kornegay JN, Avery RJ, Williams JR, Schmickel RD, Sylvester JE (1988) The homologue of the Duchenne locus is defective in X-linked muscular dystrophy of dogs. Nature 334(6178):154–156
Cossu G, Previtali SC, Napolitano S, Cicalese MP, Tedesco FS, Nicastro F, Noviello M, Roostalu U, Natali Sora MG, Scarlato M, De Pellegrin M, Godi C, Giuliani S, Ciotti F, Tonlorenzi R, Lorenzetti I, Rivellini C, Benedetti S, Gatti R, Marktel S, Mazzi B, Tettamanti A, Ragazzi M, Imro MA, Marano G, Ambrosi A, Fiori R, Sormani MP, Bonini C, Venturini M, Politi LS, Torrente Y, Ciceri F (2015) Intra-arterial transplantation of HLA-matched donor mesoangioblasts in Duchenne muscular dystrophy. EMBO Mol Med 7(12):1513–1528. https://doi.org/10.15252/emmm.201505636
Danko I, Chapman V, Wolff JA (1992) The frequency of revertants in mdx mouse genetic models for Duchenne muscular dystrophy. Pediatr Res 32(1):128–131
Deconinck AE, Rafael JA, Skinner JA, Brown SC, Potter AC, Metzinger L, Watt DJ, Dickson JG, Tinsley JM, Davies KE (1997) Utrophin-dystrophin-deficient mice as a model for Duchenne muscular dystrophy. Cell 90(4):717–727
Delalande O, Molza AE, Dos Santos Morais R, Chéron A, Pollet É, Raguenes-Nicol C, Tascon C, Giudice E, Guilbaud M, Nicolas A, Bondon A, Leturcq F, Férey N, Baaden M, Perez J, Roblin P, Piétri-Rouxel F, Hubert JF, Czjzek M, Le Rumeur E (2018) Dystrophin’s central domain forms a complex filament that becomes disorganized by in-frame deletions. J Biol Chem 293(18):6637–6646. https://doi.org/10.1074/jbc.M117.809798
Duan D (2018) Systemic AAV micro-dystrophin gene therapy for Duchenne muscular dystrophy. Mol Ther 26(10):2337–2356. https://doi.org/10.1016/j.ymthe.2018.07.011
Dunckley MG, Manoharan M, Villiet P, Eperon IC, Dickson G (1998) Modification of splicing in the dystrophin gene in cultured Mdx muscle cells by antisense oligoribonucleotides. Hum Mol Genet 7(7):1083–1090
Ferreiro V, Giliberto F, Muñiz GM, Francipane L, Marzese DM, Mampel A, Roqué M, Frechtel GD, Szijan I (2009) Asymptomatic Becker muscular dystrophy in a family with a multiexon deletion. Muscle Nerve 39(2):239–243. https://doi.org/10.1002/mus.21193
Fukada S, Morikawa D, Yamamoto Y, Yoshida T, Sumie N, Yamaguchi M, Ito T, Miyagoe-Suzuki Y, Takeda S, Tsujikawa K, Yamamoto H (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
Gaschen FP, Hoffman EP, Gorospe JR, Uhl EW, Senior DF, Cardinet GH 3rd, Pearce LK (1992) J Neurol Sci 110(1–2):149–159
Gatheridge MA, Kwon JM, Mendell JM, Scheuerbrandt G, Moat SJ, Eyskens F, Rockman-Greenberg C, Drousiotou A, Griggs RC (2016) Identifying non-duchenne muscular dystrophy-positive and false negative results in prior duchenne muscular dystrophy newborn screening programs: a review. JAMA Neurol 73(1):111–116. https://doi.org/10.1001/jamaneurol.2015.3537
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
Gentil C, Le Guiner C, Falcone S, Hogrel JY, Peccate C, Lorain S, Benkhelifa-Ziyyat S, Guigand L, Montus M, Servais L, Voit T, Piétri-Rouxel F (2016) Dystrophin threshold level necessary for normalization of neuronal nitric oxide synthase, inducible nitric oxide synthase, and ryanodine receptor-calcium release channel type 1 nitrosylation in golden retriever muscular dystrophy dystrophinopathy. Hum Gene Ther 27(9):712–726. https://doi.org/10.1089/hum.2016.041
Godfrey C, Muses S, McClorey G, Wells KE, Coursindel T, Terry RL, Betts C, Hammond S, O’Donovan L, Hildyard J, El Andaloussi S, Gait MJ, Wood MJ, Wells DJ (2015) How much dystrophin is enough: the physiological consequences of different levels of dystrophin in the mdx mouse. Hum Mol Genet 24(15):4225–4237. https://doi.org/10.1093/hmg/ddv155
Grady RM, Teng H, Nichol MC, Cunningham JC, Wilkinson RS, Sanes JR (1997) Skeletal and cardiac myopathies in mice lacking utrophin and dystrophin: a model for Duchenne muscular dystrophy. Cell 90(4):729–738
Grounds MD, Radley HG, Lynch GS, Nagaraju K, De Luca A (2008) Towards developing standard operating procedures for pre-clinical testing in the mdx mouse model of Duchenne muscular dystrophy. Neurobiol Dis 31(1):1–19. https://doi.org/10.1016/j.nbd.2008.03.008
Hakim CH, Duan D (2012) A marginal level of dystrophin partially ameliorates hindlimb muscle passive mechanical properties in dystrophin-null mice. Muscle Nerve 46(6):948–950. https://doi.org/10.1002/mus.23536
Hakim CH, Wasala NB, Pan X, Kodippili K, Yue Y, Zhang K, Yao G, Haffner B, Duan SX, Ramos J, Schneider JS, Yang NN, Chamberlain JS, Duan D (2017) A five-repeat micro-dystrophin gene ameliorated dystrophic phenotype in the severe DBA/2 J-mdx model of duchenne muscular dystrophy. Mol Ther Methods Clin Dev 6:216–230. https://doi.org/10.1016/j.omtm.2017.06.006
Hakim CH, Wasala NB, Nelson CE, Wasala LP, Yue Y, Louderman JA, Lessa TB, Dai A, Zhang K, Jenkins GJ, Nance ME, Pan X, Kodippili K, Yang NN, Chen SJ, Gersbach CA, Duan D (2018) AAV CRISPR editing rescues cardiac and muscle function for 18 months in dystrophic mice. JCI Insight 3(23):124297. https://doi.org/10.1172/jci.insight.124297
Helliwell TR, Man NT, Morris GE, Davies KE (1992) The dystrophin-related protein, utrophin, is expressed on the sarcolemma of regenerating human skeletal muscle fibres in dystrophies and inflammatory myopathies. Neuromuscul Disord 2(3):177–184
Hildyard JCW, Finch AM, Wells DJ (2019) Identification of qPCR reference genes suitable for normalizing gene expression in the mdx mouse model of Duchenne muscular dystrophy. PLoS ONE 14(1):e0211384. https://doi.org/10.1371/journal.pone.0211384
Hoffman EP, Brown RH Jr, Kunkel LM (1987) Dystrophin: the protein product of the Duchenne muscular dystrophy locus. Cell 51(6):919–928
Klymiuk N, Blutke A, Graf A, Krause S, Burkhardt K, Wuensch A, Krebs S, Kessler B, Zakhartchenko V, Kurome M, Kemter E, Nagashima H, Schoser B, Herbach N, Blum H, Wanke R, Aartsma-Rus A, Thirion C, Lochmüller H, Walter MC, Wolf E (2013) Dystrophin-deficient pigs provide new insights into the hierarchy of physiological derangements of dystrophic muscle. Hum Mol Genet 22(21):4368–4382. https://doi.org/10.1093/hmg/ddt287
Kochanek S, Clemens PR, Mitani K, Chen HH, Chan S, Caskey CT (1996) A new adenoviral vector: replacement of all viral coding sequences with 28 kb of DNA independently expressing both full-length dystrophin and beta-galactosidase. Proc Natl Acad Sci USA 93(12):5731–5736
Koenig M, Hoffman EP, Bertelson CJ, Monaco AP, Feener C, Kunkel LM (1987) Complete cloning of the Duchenne muscular dystrophy (DMD) cDNA and preliminary genomic organization of the DMD gene in normal and affected individuals. Cell 50(3):509–517
Larcher T, Lafoux A, Tesson L, Remy S, Thepenier V, François V, Le Guiner C, Goubin H, Dutilleul M, Guigand L, Toumaniantz G, De Cian A, Boix C, Renaud JB, Cherel Y, Giovannangeli C, Concordet JP, Anegon I, Huchet C (2014) Characterization of dystrophin deficient rats: a new model for Duchenne muscular dystrophy. PLoS ONE 9(10):e110371. https://doi.org/10.1371/journal.pone.0110371
Le Guiner C, Montus M, Servais L, Cherel Y, Francois V, Thibaud JL, Wary C, Matot B, Larcher T, Guigand L, Dutilleul M, Domenger C, Allais M, Beuvin M, Moraux A, Le Duff J, Devaux M, Jaulin N, Guilbaud M, Latournerie V, Veron P, Boutin S, Leborgne C, Desgue D, Deschamps JY, Moullec S, Fromes Y, Vulin A, Smith RH, Laroudie N, Barnay-Toutain F, Rivière C, Bucher S, Le TH, Delaunay N, Gasmi M, Kotin RM, Bonne G, Adjali O, Masurier C, Hogrel JY, Carlier P, Moullier P, Voit T (2014) Forelimb treatment in a large cohort of dystrophic dogs supports delivery of a recombinant AAV for exon skipping in Duchenne patients. Mol Ther 22(11):1923–1935. https://doi.org/10.1038/mt.2014.151
Le Guiner C, Servais L, Montus M, Larcher T, Fraysse B, Moullec S, Allais M, François V, Dutilleul M, Malerba A, Koo T, Thibaut JL, Matot B, Devaux M, Le Duff J, Deschamps JY, Barthelemy I, Blot S, Testault I, Wahbi K, Ederhy S, Martin S, Veron P, Georger C, Athanasopoulos T, Masurier C, Mingozzi F, Carlier P, Gjata B, Hogrel JY, Adjali O, Mavilio F, Voit T, Moullier P, Dickson G (2017) Long-term microdystrophin gene therapy is effective in a canine model of Duchenne muscular dystrophy. Nat Commun 8:16105. https://doi.org/10.1038/ncomms16105
Li D, Yue Y, Duan D (2008) Preservation of muscle force in Mdx3cv mice correlates with low-level expression of a near full-length dystrophin protein. Am J Pathol 172(5):1332–1341. https://doi.org/10.2353/ajpath.2008.071042
Li D, Yue Y, Duan D (2010) Marginal level dystrophin expression improves clinical outcome in a strain of dystrophin/utrophin double knockout mice. PLoS ONE 5(12):e15286. https://doi.org/10.1371/journal.pone.0015286
Long C, Amoasii L, Mireault AA, McAnally JR, Li H, Sanchez-Ortiz E, Bhattacharyya S, Shelton JM, Bassel-Duby R, Olson EN (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
Mah JK, Korngut L, Dykeman J, Day L, Pringsheim T, Jette N (2014) A systematic review and meta-analysis on the epidemiology of Duchenne and Becker muscular dystrophy. Neuromuscul Disord 24(6):482–491. https://doi.org/10.1016/j.nmd.2014.03.008
Mata López S, Hammond JJ, Rigsby MB, Balog-Alvarez CJ, Kornegay JN, Nghiem PP (2018) A novel canine model for Duchenne muscular dystrophy (DMD): single nucleotide deletion in DMD gene exon 20. Skelet Muscle 8(1):16. https://doi.org/10.1186/s13395-018-0162-1
McGreevy JW, Hakim CH, McIntosh MA, Duan D (2015) Animal models of Duchenne muscular dystrophy: from basic mechanisms to gene therapy. Dis Model Mech 8(3):195–213. https://doi.org/10.1242/dmm.018424
Melis MA, Cau M, Muntoni F, Mateddu A, Galanello R, Boccone L, Deidda F, Loi D, Cao A (1998) Elevation of serum creatine kinase as the only manifestation of an intragenic deletion of the dystrophin gene in three unrelated families. Eur J Paediatr Neurol 2(5):255–261
Mendell JR, Shilling C, Leslie ND, Flanigan KM, al-Dahhak R, Gastier-Foster J, Kneile K, Dunn DM, Duval B, Aoyagi A, Hamil C, Mahmoud M, Roush K, Bird L, Rankin C, Lilly H, Street N, Chandrasekar R, Weiss RB (2012) Evidence-based path to newborn screening for Duchenne muscular dystrophy. Ann Neurol 71(3):304–313
Nakamura K, Fujii W, Tsuboi M, Tanihata J, Teramoto N, Takeuchi S, Naito K, Yamanouchi K, Nishihara M (2014) Generation of muscular dystrophy model rats with a CRISPR/Cas system. Sci Rep 4:5635. https://doi.org/10.1038/srep05635
Nakamura A, Fueki N, Shiba N, Motoki H, Miyazaki D, Nishizawa H, Echigoya Y, Yokota T, Aoki Y, Takeda S (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
Nelson CE, Hakim CH, Ousterout DG, Thakore PI, Moreb EA, Castellanos Rivera RM, Madhavan S, Pan X, Ran FA, Yan WX, Asokan A, Zhang F, Duan D, Gersbach CA (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
Nelson CE, Wu Y, Gemberling MP, Oliver ML, Waller MA, Bohning JD, Robinson-Hamm JN, Bulaklak K, Castellanos Rivera RM, Collier JH, Asokan A, Gersbach CA (2019) Long-term evaluation of AAV-CRISPR genome editing for Duchenne muscular dystrophy. Nat Med 25(3):427–432. https://doi.org/10.1038/s41591-019-0344-3
Neri M, Torelli S, Brown S, Ugo I, Sabatelli P, Merlini L, Spitali P, Rimessi P, Gualandi F, Sewry C, Ferlini A, Muntoni F (2007) Dystrophin levels as low as 30% are sufficient to avoid muscular dystrophy in the human. Neuromuscul Disord 17(11–12):913–918
Nghiem PP, Bello L, Balog-Alvarez C, López SM, Bettis A, Barnett H, Hernandez B, Schatzberg SJ, Piercy RJ, Kornegay JN (2017) Whole genome sequencing reveals a 7 base-pair deletion in DMD exon 42 in a dog with muscular dystrophy. Mamm Genome 28(3–4):106–113. https://doi.org/10.1007/s00335-016-9675-2
Nicholson LV, Johnson MA, Bushby KM, Gardner-Medwin D, Curtis A, Ginjaar IB, den Dunnen JT, Welch JL, Butler TJ, Bakker E, van Ommen GJB, Harris JB (1993) Integrated study of 100 patients with Xp21 linked muscular dystrophy using clinical, genetic, immunochemical, and histopathological data. Part 3. Differential diagnosis and prognosis. J Med Genet 30(9):745–751
Partridge TA, Morgan JE, Coulton GR, Hoffman EP, Kunkel LM (1989) Conversion of mdx myofibres from dystrophin-negative to -positive by injection of normal myoblasts. Nature 337(6203):176–179
Pegoraro E, Schimke RN, Garcia C, Stern H, Cadaldini M, Angelini C, Barbosa E, Carroll J, Marks WA, Neville HE, Marks H, Appleton S, Toriello H, Wessel HB, Donnelly J, Bernes SM, Taber JW, Weiss L, Hoffman EP (1995) Genetic and biochemical normalization in female carriers of Duchenne muscular dystrophy: evidence for failure of dystrophin production in dystrophin-competent myonuclei. Neurology. 45(4):677–690
Ramos JN, Hollinger K, Bengtsson NE, Allen JM, Hauschka SD, Chamberlain JS (2019) Development of novel micro-dystrophins with enhanced functionality. Mol Ther 27(3):623–635. https://doi.org/10.1016/j.ymthe.2019.01.002
Rodrigues M, Echigoya Y, Maruyama R, Lim KR, Fukada SI, Yokota T (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
Sacco A, Mourkioti F, Tran R, Choi J, Llewellyn M, Kraft P, Shkreli M, Delp S, Pomerantz JH, Artandi SE, Blau HM (2010) Short telomeres and stem cell exhaustion model Duchenne muscular dystrophy in mdx/mTR mice. Cell 143(7):1059–1071. https://doi.org/10.1016/j.cell.2010.11.039
Sardone V, Ellis M, Torelli S, Feng L, Chambers D, Eastwood D, Sewry C, Phadke R, Morgan JE, Muntoni F (2018) A novel high-throughput immunofluorescence analysis method for quantifying dystrophin intensity in entire transverse sections of Duchenne muscular dystrophy muscle biopsy samples. PLoS ONE 13(3):e0194540. https://doi.org/10.1371/journal.pone.0194540
Sharp NJ, Kornegay JN, Van Camp SD, Herbstreith MH, Secore SL, Kettle S, Hung WY, Constantinou CD, Dykstra MJ, Roses AD et al (1992) An error in dystrophin mRNA processing in golden retriever muscular dystrophy, an animal homologue of Duchenne muscular dystrophy. Genomics 13(1):115–121
Sharp PS, Bye-a-Jee H, Wells DJ (2011) Physiological characterization of muscle strength with variable levels of dystrophin restoration in mdx mice following local antisense therapy. Mol Ther 19(1):165–171. https://doi.org/10.1038/mt.2010.213
Sicinski P, Geng Y, Ryder-Cook AS, Barnard EA, Darlison MG, Barnard PJ (1989) The molecular basis of muscular dystrophy in the mdx mouse: a point mutation. Science 244(4912):1578–1580
Sui T, Lau YS, Liu D, Liu T, Xu L, Gao Y, Lai L, Li Z, Han R (2018) A novel rabbit model of Duchenne muscular dystrophy generated by CRISPR/Cas9. Dis Model Mech 11(6):dmm032201. https://doi.org/10.1242/dmm.032201
Tabebordbar M, Zhu K, Cheng JKW, Chew WL, Widrick JJ, Yan WX, Maesner C, Wu EY, Xiao R, Ran FA, Cong L, Zhang F, Vandenberghe LH, Church GM, Wagers AJ (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
van der Pijl EM, van Putten M, Niks EH, Verschuuren JJGM, Aartsma-Rus A, Plomp JJ (2018) Low dystrophin levels are insufficient to normalize the neuromuscular synaptic abnormalities of mdx mice. Neuromuscul Disord 28(5):427–442. https://doi.org/10.1016/j.nmd.2018.02.013
van Putten M, Hulsker M, Nadarajah VD, van Heiningen SH, van Huizen E, van Iterson M, Admiraal P, Messemaker T, den Dunnen JT, ‘t Hoen PA, Aartsma-Rus A (2012) The effects of low levels of dystrophin on mouse muscle function and pathology. PLoS ONE 7(2):e31937. https://doi.org/10.1371/journal.pone.0031937
van Putten M, Hulsker M, Young C, Nadarajah VD, Heemskerk H, van der Weerd L, ‘t Hoen PA, van Ommen GJ, Aartsma-Rus AM (2013) Low dystrophin levels increase survival and improve muscle pathology and function in dystrophin/utrophin double-knockout mice. FASEB J 27(6):2484–2495. https://doi.org/10.1096/fj.12-224170
van Putten M, van der Pijl EM, Hulsker M, Verhaart IE, Nadarajah VD, van der Weerd L, Aartsma-Rus A (2014) Low dystrophin levels in heart can delay heart failure in mdx mice. J Mol Cell Cardiol 69:17–23. https://doi.org/10.1016/j.yjmcc.2014.01.009
van Putten M, Putker K, Overzier M, Adamzek WA, Pasteuning-Vuhman S, Plomp JJ, Aartsma-Rus A (2019) Natural disease history of the D2 -mdx mouse model for Duchenne muscular dystrophy. FASEB J. https://doi.org/10.1096/fj.201802488r
Vila MC, Klimek MB, Novak JS, Rayavarapu S, Uaesoontrachoon K, Boehler JF, Fiorillo AA, Hogarth MW, Zhang A, Shaughnessy C, Gordish-Dressman H, Burki U, Straub V, Lu QL, Partridge TA, Brown KJ, Hathout Y, van den Anker J, Hoffman EP, Nagaraju K (2015) Elusive sources of variability of dystrophin rescue by exon skipping. Skelet Muscle. 5:44. https://doi.org/10.1186/s13395-015-0070-6
Walmsley GL, Arechavala-Gomeza V, Fernandez-Fuente M, Burke MM, Nagel N, Holder A, Stanley R, Chandler K, Marks SL, Muntoni F, Shelton GD, Piercy RJ (2010) A duchenne muscular dystrophy gene hot spot mutation in dystrophin-deficient cavalier king charles spaniels is amenable to exon 51 skipping. PLoS ONE 5(1):e8647
Wang B, Li J, Xiao X (2000) Adeno-associated virus vector carrying human minidystrophin genes effectively ameliorates muscular dystrophy in mdx mouse model. Proc Natl Acad Sci USA 97(25):13714–13719
Wasala NB, Zhang K, Wasala LP, Hakim CH, Duan D (2015) The FVB Background Does Not Dramatically Alter the Dystrophic Phenotype of Mdx Mice. PLoS Curr. https://doi.org/10.1371/currents.md.28266819ca0ec5fefcac767ea9a3461c
Wasala NB, Yue Y, Vance J, Duan D (2017) Uniform low-level dystrophin expression in the heart partially preserved cardiac function in an aged mouse model of Duchenne cardiomyopathy. J Mol Cell Cardiol 102:45–52. https://doi.org/10.1016/j.yjmcc.2016.11.011
Weiss RB, Vieland VJ, Dunn DM, Kaminoh Y, Flanigan KM, United Dystrophinopathy Project (2018) Long-range genomic regulators of THBS1 and LTBP4 modify disease severity in duchenne muscular dystrophy. Ann Neurol 84(2):234–245
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
Wells DJ (2018) Tracking progress: an update on animal models for Duchenne muscular dystrophy. Dis Model Mech 11(6):035774. https://doi.org/10.1242/dmm.035774
Yucel N, Chang AC, Day JW, Rosenthal N, Blau HM (2018) Humanizing the mdx mouse model of DMD: the long and the short of it. NPJ Regen Med 3:4. https://doi.org/10.1038/s41536-018-0045-4
Yue Y, Pan X, Hakim CH, Kodippili K, Zhang K, Shin JH, Yang HT, McDonald T, Duan D (2015) Safe and bodywide muscle transduction in young adult Duchenne muscular dystrophy dogs with adeno-associated virus. Hum Mol Genet 24(20):5880–5890. https://doi.org/10.1093/hmg/ddv310
Zimowski JG, Pilch J, Pawelec M, Purzycka JK, Kubalska J, Ziora-Jakutowicz K, Dudzińska M, Zaremba J (2017) A rare subclinical or mild type of Becker muscular dystrophy caused by a single exon 48 deletion of the dystrophin gene. J Appl Genet 58(3):343–347. https://doi.org/10.1007/s13353-017-0391-8
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Wells, D.J. What is the level of dystrophin expression required for effective therapy of Duchenne muscular dystrophy?. J Muscle Res Cell Motil 40, 141–150 (2019). https://doi.org/10.1007/s10974-019-09535-9
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DOI: https://doi.org/10.1007/s10974-019-09535-9