19
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: not found

      Gene Therapy for Muscular Dystrophies: Progress and Challenges

      review-article
      , MD, PhD a , , , MD b
      Journal of Clinical Neurology (Seoul, Korea)
      Korean Neurological Association
      gene therapy, muscular dystrophies, Duchenne

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          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 devastating diseases.

          Related collections

          Most cited references39

          • Record: found
          • Abstract: found
          • Article: not found

          Gene transfer into muscle by electroporation in vivo.

          Among the nonviral techniques for gene transfer in vivo, the direct injection of plasmid DNA into muscle is simple, inexpensive, and safe. Applications of this method have been limited by the relatively low expression levels of the transferred gene. We investigated the applicability of in vivo electroporation for gene transfer into muscle, using plasmid DNA expressing interleukin-5 (IL-5) as the vector. The tibialis anterior muscles of mice were injected with the plasmid DNA, and then a pair of electrode needles were inserted into the DNA injection site to deliver electric pulses. Five days later, the serum IL-5 levels were assayed. Mice that did not receive electroporation had serum levels of 0.2 ng/ml. Electroporation enhanced the levels to over 20 ng/ml. Histochemical analysis of muscles injected with a lacZ expression plasmid showed that in vivo electroporation increased both the number of muscle fibers taking up plasmid DNA and the copy number of plasmids introduced into the cells. These results demonstrate that gene transfer into muscle by electroporation in vivo is more efficient than simple intramuscular DNA injection.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Systemic delivery of genes to striated muscles using adeno-associated viral vectors.

            A major obstacle limiting gene therapy for diseases of the heart and skeletal muscles is an inability to deliver genes systemically to muscles of an adult organism. Systemic gene transfer to striated muscles is hampered by the vascular endothelium, which represents a barrier to distribution of vectors via the circulation. Here we show the first evidence of widespread transduction of both cardiac and skeletal muscles in an adult mammal, after a single intravenous administration of recombinant adeno-associated virus pseudotype 6 vectors. The inclusion of vascular endothelium growth factor/vascular permeability factor, to achieve acute permeabilization of the peripheral microvasculature, enhanced tissue transduction at lower vector doses. This technique enabled widespread muscle-specific expression of a functional micro-dystrophin in the skeletal muscles of dystrophin-deficient mdx mice, which model Duchenne muscular dystrophy. We propose that these methods may be applicable for systemic delivery of a wide variety of genes to the striated muscles of adult mammals.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Aminoglycoside antibiotics restore dystrophin function to skeletal muscles of mdx mice.

              Duchenne muscular dystrophy (DMD) is caused by mutations in the dystrophin gene, leading to the absence of the dystrophin protein in striated muscle. A significant number of these mutations are premature stop codons. On the basis of the observation that aminoglycoside treatment can suppress stop codons in cultured cells, we tested the effect of gentamicin on cultured muscle cells from the mdx mouse - an animal model for DMD that possesses a premature stop codon in the dystrophin gene. Exposure of mdx myotubes to gentamicin led to the expression and localization of dystrophin to the cell membrane. We then evaluated the effects of differing dosages of gentamicin on expression and functional protection of the muscles of mdx mice. We identified a treatment regimen that resulted in the presence of dystrophin in the cell membrane in all striated muscles examined and that provided functional protection against muscular injury. To our knowledge, our results are the first to demonstrate that aminoglycosides can suppress stop codons not only in vitro but also in vivo. Furthermore, these results raise the possibility of a novel treatment regimen for muscular dystrophy and other diseases caused by premature stop codon mutations. This treatment could prove effective in up to 15% of patients with DMD.
                Bookmark

                Author and article information

                Journal
                J Clin Neurol
                JCN
                Journal of Clinical Neurology (Seoul, Korea)
                Korean Neurological Association
                1738-6586
                2005-5013
                September 2010
                01 October 2010
                : 6
                : 3
                : 111-116
                Affiliations
                [a ]Department of Neurology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea.
                [b ]Department of Neurology, Incheon Medical Center, Incheon, Korea.
                Author notes
                Correspondence: Kyung Seok Park, MD, PhD. Department of Neurology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, 300 Gumi-dong, Bundang-gu, Seongnam 463-707, Korea. Tel +82-31-787-7469, Fax +82-31-718-9327, pks1126@ 123456chol.com
                Article
                10.3988/jcn.2010.6.3.111
                2950915
                20944811
                532b7e0a-f0c1-49ec-8555-b99daf7b5fd3
                Copyright © 2010 Korean Neurological Association
                History
                : 10 January 2010
                : 24 June 2010
                : 24 June 2010
                Categories
                Review

                Neurology
                gene therapy,duchenne,muscular dystrophies
                Neurology
                gene therapy, duchenne, muscular dystrophies

                Comments

                Comment on this article