Immune responses to dystrophin: implications for gene therapy of Duchenne muscular dystrophy

Ferrer, A; Wells, Kim E.; Wells, Daniel

doi:10.1038/sj.gt.3301259

Cited by 80 publications

(61 citation statements)

References 36 publications

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“…At 1 week postinjection, mice injected with either construct showed similar numbers of dystrophin-positive fibres (Figure 4a and b). However, by 8 weeks postinjection, the number of human dystrophin-positive fibres had dropped significantly (Po0.001, Figure 4b), consistent with our previously reported data for intramuscular injection of plasmid DNA, 18 whereas no difference was found in the number of murine dystrophin-expressing fibres between both time points (Figure 4a). At 8 weeks postinjection of murine dystrophin, there was a nonsignificant increase in CD8 þ infiltrate in the treated mdx muscle (51.6749.4 additional CD8 þ cells per mm 2 ) above that of the untreated muscle and a similar pattern was seen 8 weeks postinjection of the human dystrophin construct (40.3723.4 additional CD8 þ cells per mm 2 ).…”

Section: Does the Hyaluronidase And Electrotransfer Procedures Increassupporting

confidence: 91%

“…24 In most cases, it was not clear if the immune response was directed to the transgene itself or if this immune response was enhanced due to the vector system used, that is, cellular components or viral coat proteins. We and others have demonstrated that following the direct intramuscular injection of naked plasmid DNA expressing dystrophin in the mdx mouse, an immune response leads to a loss of fibres transfected with human dystrophin by 8 weeks postinjection, 18,19 but no immune response to murine dystrophin was detectable by 12 weeks. 18 However, the overall numbers of dystrophin-positive fibres obtained by direct intramuscular injection of plasmid DNA was very low and so there was a formal possibility that the expression of greater amounts of antigen could break the tolerance observed in this experiment.…”

Section: Introductionmentioning

confidence: 90%

“…We and others have demonstrated that following the direct intramuscular injection of naked plasmid DNA expressing dystrophin in the mdx mouse, an immune response leads to a loss of fibres transfected with human dystrophin by 8 weeks postinjection, 18,19 but no immune response to murine dystrophin was detectable by 12 weeks. 18 However, the overall numbers of dystrophin-positive fibres obtained by direct intramuscular injection of plasmid DNA was very low and so there was a formal possibility that the expression of greater amounts of antigen could break the tolerance observed in this experiment. In the current study, plasmid DNA encoding full-length murine or human dystrophin driven by the CMV promoter was electroporated into the tibialis anterior (TA) muscles of mdx mice 2 h after treatment with hyaluronidase, as this procedure has been shown to achieve high transfection efficiencies in muscle.…”

Section: Introductionmentioning

confidence: 90%

“…Despite the higher number of fibres transfected with murine dystrophin after the combined hyaluronidase and electrotransfer procedure compared with multiple direct injection, 18 only a very low level of antibodies against murine dystrophin was detected by Western blot analysis when the murine dystrophin construct was …”

Section: Does the Hyaluronidase And Electrotransfer Procedures Increasmentioning

confidence: 99%

“…6 There are many strategies for the induction of de novo dystrophin expression as a therapeutic approach for the treatment of DMD. These include systemic drug delivery, 7 gene modification at DNA and RNA levels, [8][9][10][11] cell transplantation [12][13][14] and gene delivery with a wide range of both viral [15][16][17] and nonviral [18][19][20] delivery systems. However, therapeutic levels, together with a stable longterm presence of dystrophin at the sarcolemma of the muscle fibres, are essential.…”

Section: Introductionmentioning

confidence: 99%

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Long-term expression of full-length human dystrophin in transgenic mdx mice expressing internally deleted human dystrophins

et al. 2004

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Section: Does the Hyaluronidase And Electrotransfer Procedures Increassupporting

confidence: 91%

Section: Introductionmentioning

confidence: 90%

Section: Introductionmentioning

confidence: 90%

Section: Does the Hyaluronidase And Electrotransfer Procedures Increasmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Long-term expression of full-length human dystrophin in transgenic mdx mice expressing internally deleted human dystrophins

et al. 2004

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Gene transfer to skeletal muscle

Chamberlain

2005

Encyclopedia of Genetics, Genomics, Proteomics and Bioinformatics

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Muscle tissue is an important target for gene therapy applications due to the large number of disorders of skeletal and cardiac muscle. These include inherited disorders such as Duchenne muscular dystrophy (DMD) and acquired disorders such as heart failure and age‐associated muscle weakness (sarcopenia). A potentially powerful approach to treating these various conditions involves delivery of a gene or genes to the affected muscles. In the case of a genetic disorder, the goal may be to deliver a normal version of the defective gene. In other cases, benefit might result from delivery of a gene that could augment normal muscle function, such as a growth factor gene. Other applications include delivery of DNA fragments that could modulate gene expression or lead to correction of a genetic mutation. Since muscle tissue represents nearly 40% of the total body mass, gene transfer to muscle is an enormously challenging proposition. Consequently, numerous types of gene or DNA vectors and delivery strategies are being explored for gene therapy of muscle disorders. No single gene vector or delivery method is likely to be universally applicable for all conditions, but some have been developed to greater degrees than others. This article briefly reviews the major vectors and delivery methods currently being developed for gene therapy of muscle diseases.

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Gene Therapy for Duchenne Muscular Dystrophy

Putten

Aartsma‐Rus

2013

Encyclopedia of Life Sciences

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Duchenne muscular dystrophy is a severe muscle wasting disorder caused by lack of functional dystrophin, due to reading‐frame disrupting mutations in the DMD gene. There is no cure, but several genetic therapeutic approaches aiming to delay disease progression by restoring, manipulating or replacing the DMD gene are under investigation in (pre)clinical settings. The antisense‐mediated exon skipping approach, which restores the disrupted reading frame allowing synthesis of partly functional dystrophin proteins is closest to clinical application. The first trials with viral vectors to deliver minidystrophin genes and compounds to force readthrough of premature stop codons by the translation machinery have also been undertaken, whereas other approaches, like genome editing, are still in the early development phase. Despite some remaining hurdles that have to be overcome, lessons learned can be used to catalyse the development of potential therapies. Key Concepts: Duchenne muscular dystrophy (DMD) is caused by reading‐frame disrupting mutations in the DMD gene, resulting in premature termination of dystrophin synthesis. Inframe mutations allow synthesis of shorter, but partly functional dystrophin proteins, resulting in the milder Becker muscular dystrophy (BMD) phenotype. Antisense oligonucleotide‐mediated exon skipping aims to restore the reading frame enabling synthesis of BMD‐like dystrophins, thereby converting the severe DMD into the milder BMD disease. Gene replacement therapy (replacing the dysfunctional dystrophin cDNA) is hampered by the size and complexity of the DMD gene and dystrophin cDNA. AAV vectors have a limited loading capacity of ∼4.5 kb, requiring the use of mini‐, or microdystrophin genes that encode only the most crucial functional domains. Ataluren can be used to force the translational machinery to ignore premature stop codons enabling synthesis of intact dystrophin. Endonuclease‐mediated generation of double‐strand breaks can be used to correct the genetic mutation or restore the reading frame. Many therapeutic approaches have progressed to clinical trials.

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Immune responses to dystrophin: implications for gene therapy of Duchenne muscular dystrophy

Cited by 80 publications

References 36 publications

Long-term expression of full-length human dystrophin in transgenic mdx mice expressing internally deleted human dystrophins

Long-term expression of full-length human dystrophin in transgenic mdx mice expressing internally deleted human dystrophins

Gene transfer to skeletal muscle

Gene Therapy for Duchenne Muscular Dystrophy

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