J Clin Neurol.  2010 Sep;6(3):111-116. 10.3988/jcn.2010.6.3.111.

Gene Therapy for Muscular Dystrophies: Progress and Challenges

• Park KS
• Oh D

• KMID: 1462846
• DOI: http://doi.org/10.3988/jcn.2010.6.3.111

Abstract

Muscular dystrophies are groups of inherited progressive diseases of the muscle caused by mutations of diverse genes related to normal muscle function. Although there is no current effective treatment for these devastating diseases, various molecular strategies have been developed to restore the expressions of the associated defective proteins. In preclinical animal models, both viral and nonviral vectors have been shown to deliver recombinant versions of defective genes. Antisense oligonucleotides have been shown to modify the splicing mechanism of mesenger ribonucleic acid to produce an internally deleted but partially functional dystrophin in an experimental model of Duchenne muscular dystrophy. In addition, chemicals can induce readthrough of the premature stop codon in nonsense mutations of the dystrophin gene. On the basis of these preclinical data, several experimental clinical trials are underway that aim to demonstrate efficacy in treating these de-vastating diseases.

Keyword

gene therapy; muscular dystrophies; Duchenne

MeSH Terms

Codon, Nonsense
Dystrophin
Genetic Therapy
Models, Animal
Models, Theoretical
Muscles
Muscular Dystrophies
Muscular Dystrophy, Duchenne
Oligonucleotides, Antisense
Proteins
RNA
Codon, Nonsense
Dystrophin
Oligonucleotides, Antisense
Proteins
RNA

Figure

• 

  Fig. 1 Full-length and truncated dystrophin genes. A: Full-length dystrophin gene. B: Minidystrophin gene. C: Microdystrophin gene. ABD: N-terminal actin-binding domain, H1-H4: hinge regions, 1-24: spectrin-like repeats, iABD: internal actin-binding domain, CR: cysteine-rich region, CT: carboxy terminus.

• 

  Fig. 2 Exon skipping using antisense oligonucleotides. A: An out-of-frame deletion of exons 45-54 causes a stop codon in exon 55 that arrests dystrophin pro-duction in Duchenne muscular dystrophy. B: Skipping of exon 44 using antisense oligonucleotides restores the reading frame back "in-frame", producing a partially functional dystrophin protein. AON: antisense oligonucleotide.

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