Inherited Muscle Disease: Gene Therapy


Muscular dystrophies have been an area of special interest for genetic therapies. The abundance of skeletal muscle tissue in the body presents particular problems for this form of treatment.

Keywords: muscular dystrophy; duchenne; dystrophin; gene therapy; cell transfer

Figure 1.

Hypothetical view of the dystrophin‐associated complex of proteins and glycoproteins at the surface of the muscle fibre. Dystrophin, the protein that is lacking in Duchenne muscular dystrophy and is defective in the milder Becker muscular dystrophy, appears to be the key protein required for effective assembly of this complex, elucidation of which has proved an interesting example of the interaction between positional cloning and biochemical investigation. Mutations in the genes for the various sarcoglycans have been found to underlie some of the limb‐girdle muscular dystrophies (LGMD): α‐Sarcoglycan – LGMD 2D, β‐Sarcoglycan – LGMD 2E, γ‐Sarcoglycan – LGMD 2C, δ‐Sarcoglycan – LGMD 2F. A large proportion of congenital muscular dystrophy cases have proved to involve mutations in the α‐chain of merosin, the link of this complex into the basement membrane. The muscle‐specific isoform of neural nitric oxide synthase, μNOS, and the dystrophin‐like protein, dystroglycan, are also linked into this complex and disruption of this complex may compromise their functions and perhaps contribute to some aspects of the pathology of the dystrophinopathies. Other dystrophies are ascribed to proteins that do not appear to be part of this complex, some associated with the cell surface, some with the nuclear membranes and some with the sarcoplasm (for review, see Cohn and Campbell (2000) Molecular basis of muscular dystrophies. Muscle and Nerve 23: 1456–1471).



Aartsma‐Rus A, Kaman WE, Weij R et al. (2006) Exploring the frontiers of therapeutic exon skipping for Duchenne muscular dystrophy by double targeting within one or multiple exons. Molecular Therapy. 14(3): 401–407.

Alter J, Lou F, Rabinowitz A et al. (2006) Systemic delivery of morpholino oligonucleotide restores dystrophin expression bodywide and improves dystrophic pathology. Nature Medicine 12(2): 175–177.

Bertoni C, Lau C, Rando AT et al. (2003) Restoration of dystrophin expression in mdx muscle cells by chimeraplast‐mediated exon skipping. Human Molecular Genetics 12(10): 1087–1099.

Burkin DJ, Wallace GQ, Nicol KJ, Kaufman DJ and Kaufman SJ (2001) Enhanced expression of the a7b1 integrin reduces muscular dystrophy and restores viability in dystrophic mice. Journal of Cell Biology 152: 1207–1218.

Chen HH, Mack LM, Kelly R et al. (1997) Persistence in muscle of an adenoviral vector that lacks all viral genes. Proceedings of the National Academy of Sciences of the USA 94: 1645–1650.

Dezawa M, Ishikawa H, Itokazu Y et al. (2005) Bone marrow stromal cells generate muscle cells and repair muscle degeneration. Science 309(5732): 314–317.

Dunckley MG, Manoharan M, Villiet P, Eperon IC and Dickson G (1998) Modification of splicing in the dystrophin gene in cultured Mdx muscle cells by antisense oligoribonucleotides. Human Molecular Genetics 7: 1083–1090.

England SB, Nicholson LVB, Johnson MA et al. (1990) Very mild muscular dystrophy associated with deletion of 46% of dystrophin. Nature 343: 180–182.

Fassati A and Bresolin N (2000) Retroviral vectors for gene therapy of Duchenne muscular dystrophy. Neurological Sciences 21(suppl. 5): S925–S927.

Ferrari G, Cusella‐De Angelis G, Coletta M et al. (1998) Muscle regeneration by bone marrow‐derived myogenic precursors. Science 279: 1528–1530.

Galvez BG, Sampaolesi M, Brunelli S et al. (2006) Complete repair of dystrophic skeletal muscle by mesoangioblasts with enhanced migration ability. Journal of Cell Biology 174(2): 231–243.

Goyenvalle A, Vulin A, Fougerousse F et al. (2004) Rescue of dystrophic muscle through U7 snRNA‐mediated exon skipping. Science 306(5702): 1796–1799.

Gregorevic P, Allen JM, Harper SQ et al. (2006) rAAV6‐microdystrophin preserves muscle function and extends lifespan in severely dystrophic mice. Nature Medicine 12(7): 787–789.

Gussoni E, Pavlath GK, Lanctot AM et al. (1992) Normal dystrophin transcripts detected in Duchenne muscular dystrophy patients after myoblast transplantation. Nature 356: 435–438.

Gussoni E, Soneoka Y, Strickland CD et al. (1999) Dystrophin expression in the mdx mouse restored by stem cell transplantation. Nature 410: 390–394.

Hagstrom JE, Hegge J, Zhang G et al. (2004) A facile nonviral method for delivering genes and siRNAs to skeletal muscle of mammalian limbs. Molecular Therapy 10(2): 386–398.

Huard J, Krisky D, Oligino T et al. (1997) Gene transfer to muscle using herpes simplex virus‐based vectors. Neuromuscular Disorders 7: 299–313.

Khurana TS and Davies KE (2003) Pharmacological strategies for muscular dystrophy. Nature Reviews Drug Discovery 2(5): 379–390.

Koenig M, Hoffman EP, Bertelson CJ et al. (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: 509–517.

Law PK, Goodwin TG, Fang Q et al. (1997) Human gene therapy with myoblast transfer. Transplantation Proceedings 29: 2234–2237.

Lu QL, Mann CJ, Lou F et al. (2003) Functional amounts of dystrophin produced by skipping the mutated exon in the mdx dystrophic mouse. Nature Medicine 9(8): 1009–1014.

MacKenzie TC, Kobinger GP, Kootstra NA et al. (2005) Transduction of satellite cells after prenatal intramuscular administration of lentiviral vectors. Journal of Genetic Medicine 7(1): 50–58.

Monaco AP, Bertelson CJ, Liechti‐Gallati S, Moser H and Kunkel LM (1988) An explanation for the phenotypic differences between patients bearing partial deletions of the DMD locus. Genomics 2: 90–95.

Partridge TA, Morgan JE, Coulton GR et al. (1989) Conversion of mdx myofibres from dystrophin‐negative to ‐positive by injection of normal myoblasts. Nature 337(6203): 176–179.

Rabinowitz JE, Rolling F, Li C et al. (2002) Cross‐packaging of a single adeno‐associated virus (AAV) type 2 vector genome into multiple AAV serotypes enables transduction with broad specificity. Journal of Virology 76(2): 791–801.

Sampaolesi M, Blot S, D'Antona G et al. (2006) Mesoangioblast stem cells ameliorate muscle function in dystrophic dogs. Nature 444(7119): 574–579.

Skuk D, Goulet M, Roy B et al. (2006) Dystrophin expression in muscles of duchenne muscular dystrophy patients after high‐density injections of normal myogenic cells. Journal of Neuropathology & Experimental Neurology 65(4): 371–386.

Stedman H, Wilson JM, Finke R, Kleckner AL and Mendell J (2000) Phase I clinical trial utilizing gene therapy for limb girdle muscular dystrophy: alpha‐, beta‐, gamma‐ or delta‐sarcoglycan gene delivered with intramuscular instillations of adeno‐ associated vectors. Human Gene Therapy 11: 777–790.

Tinsley J, Deconinck N, Fisher R et al. (1998) Expression of full‐length utrophin prevents muscular dystrophy in mdx mice. Nature Medicine 4: 1441–1444.

Wang B, Li J and Xiao X (2000) Adeno‐associated virus vector carrying human minidystrophin genes effectively ameliorates muscular dystrophy in mdx mouse model. Proceedings of the National Academy of Sciences of the USA 97: 13714–13719.

Welch EM, Barton ER, Zhuo J et al. (2007) PTC124 is a novel therapeutic for the treatment of genetic disorders caused by nonsense mutations. Nature 447(7140): 87–91.

Yuasa K, Sakamoto M, Miyagoe‐Suzuki Y et al. (2002) Adeno‐associated virus vector‐mediated gene transfer into dystrophin‐deficient skeletal muscles evokes enhanced immune response against the transgene product. Gene Therapy 9(23): 1576–1588.

Zhang G, Budker V, Williams P, Subbotin V and Wolff JA (2001) Efficient expression of naked DNA delivered intraarterially to limb muscles of nonhuman primates. Human Gene Therapy 12: 427–438.

Further Reading

Ahn AH and Kunkel LM (1993) The structural and functional diversity of dystrophin. Nature Genetics 3: 283–291.

Bartlett RJ, Stockinger S, Denis MM et al. (2000) In vivo targeted repair of a point mutation in the canine dystrophin gene by a chimeric RNA/DNA oligonucleotide. Nature Biotechnology 18: 615–622.

Barton‐Davis ER, Cordier L, Shoturma DI, Leland SE and Sweeney HL (1999) Aminoglycoside antibiotics restore dystrophin function to skeletal muscles of mdx mice. Journal of Clinical Investigation 104: 375–381.

Barton‐Davis ER, Shoturma DI, Musaro A, Rosenthal N and Sweeney HL (1998) Viral mediated expression of insulin‐like growth factor I blocks the aging‐related loss of skeletal muscle function. Proceedings of the National Academy of Sciences of the USA 95(26): 15603–15607.

Bittner RE, Schöfer C, Weipoltshammer K et al. (1999) Recruitment of bone‐marrow‐derived cells by skeletal and cardiac muscle in adult dystrophic mdx mice. Anatomy and Embryology 199: 391–396.

Budker V, Zhang G, Danko I, Williams P and Wolff J (1998) The efficient expression of intravascularly delivered DNA in rat muscle. Gene Therapy 5: 272–276 Links .

Cohn RD and Campbell KP (2000) Molecular basis of muscular dystrophies. Muscle and Nerve 23: 1456–1471.

Dunckley MG, Wells DJ, Walsh FS and Dickson G (1993) Direct retroviral‐mediated transfer of a dystrophin minigene into mdx mouse muscle in vivo. Human Molecular Genetics 2: 717–723.

Dystrophin (muscular dystrophy, Duchenne and Becker types) (DMD); Locus ID: 1756. LocusLink:

Dystrophin (muscular dystrophy, Duchenne and Becker types) (DMD); MIM number: 300377. OMIM:‐post/Omim/dispmim?300377

Exon skipping with 2′O‐methyl phosphorothioate antisense oligonucleotides to restore open reading frame in the mutated dystrophin gene

Feero WG, Rosenblatt JD, Huard J et al. (1997) Viral gene delivery to skeletal muscle: insights on maturation‐ dependent loss of fiber infectivity for adenovirus and herpes simplex type 1 viral vectors. Human Gene Therapy 8: 371–380.

Greelish JP, Su LT, Lankford EB et al. (1999) Stable restoration of the sarcoglycan complex in dystrophic muscle perfused with histamine and a recombinant adeno‐associated viral vector. Nature Medicine 5: 439–443.

Hartigan‐O’Connor D, Amalfitano A and Chamberlain JS (1999) Improved production of gutted adenovirus in cells expressing adenovirus preterminal protein and DNA polymerase. Journal of Virology 73: 7835–7841.

Jiang ZL, Reay D, Kreppel F et al. (2001) Local high‐capacity adenovirus‐mediated mCTLA4Ig and mCD40Ig expression prolongs recombinant gene expression in skeletal muscle. Molecular Therapy 3: 892–900.

Mendell JR, Kissel JT, Amato AA et al. (1995) Myoblast transfer in the treatment of Duchenne's muscular dystrophy. New England Journal of Medicine 333: 832–838.

Moser H (1984) Duchenne muscular dystrophy: pathogenetic aspects and genetic prevention. Human Genetics 66: 17–40.

Neuromuscular Disorders. Gene tables for neuromuscular disorders

Partridge TA (1991) Myoblast transfer: a possible therapy for inherited myopathies? Muscle and Nerve 14: 197–212.

Phase 2 clinical trial of PTC124 to promote read‐through of stop mutations in DMD

Trial of AAV delivery of a microdystrophin expression construct by intramuscular injection in DMD boys

Trial of AAV therapy for gamma‐sarcoglycanopathy

Trial on use of morpholino antisense oligonucleotides to induce skipping of exons such as to restore open reading frame in the mutated dystrophin gene

Walton J and Gardner‐Medwin D (1981) The muscular dystrophies. In: Walton JN (ed.) Disorders of Voluntary Muscle, pp. 481–524. Edinburgh, UK: Churchill Livingstone.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Partridge, Terence(Sep 2007) Inherited Muscle Disease: Gene Therapy. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0005753.pub2]