T.P.2.04 Optimization of antisense-mediated exon skipping in mouse models for Duchenne muscular dystrophy

2008 ◽  
Vol 18 (9-10) ◽  
pp. 757
Author(s):  
A. Aartsma-Rus ◽  
H.A. Heemskerk ◽  
C.L. de Winter ◽  
M. van Putten ◽  
S. De Kimpe ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Mouse Models ◽  
Exon Skipping

scholarly journals Peptide-conjugated phosphodiamidate oligomer-mediated exon skipping has benefits for cardiac function in mdx and Cmah-/-mdx mouse models of Duchenne muscular dystrophy

PLoS ONE ◽  
2018 ◽  
Vol 13 (6) ◽  
pp. e0198897 ◽  
Author(s):  
Alison M. Blain ◽  
Elizabeth Greally ◽  
Graham McClorey ◽  
Raquel Manzano ◽  
Corinne A. Betts ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Cardiac Function ◽  
Mouse Models ◽  
Exon Skipping ◽  
Mdx Mouse

Dantrolene Enhances Antisense-Mediated Exon Skipping in Human and Mouse Models of Duchenne Muscular Dystrophy

2012 ◽  
Vol 4 (164) ◽  
pp. 164ra160-164ra160 ◽  
Author(s):  
G. C. Kendall ◽  
E. I. Mokhonova ◽  
M. Moran ◽  
N. E. Sejbuk ◽  
D. W. Wang ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Mouse Models ◽  
Exon Skipping ◽  
Human And Mouse

scholarly journals Evaluating the potential of novel genetic approaches for the treatment of Duchenne muscular dystrophy

2021 ◽  
Author(s):  
Vratko Himič ◽  
Kay E. Davies
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Structural Integrity ◽  
Viral Vector ◽  
Exon Skipping ◽  
Dystrophin Gene ◽  
Pharmacological Treatments ◽  
Genetic Sequencing ◽  
Reading Frame ◽  
Target Effects

AbstractDuchenne muscular dystrophy (DMD) is an X-linked progressive muscle-wasting disorder that is caused by a lack of functional dystrophin, a cytoplasmic protein necessary for the structural integrity of muscle. As variants in the dystrophin gene lead to a disruption of the reading frame, pharmacological treatments have only limited efficacy; there is currently no effective therapy and consequently, a significant unmet clinical need for DMD. Recently, novel genetic approaches have shown real promise in treating DMD, with advancements in the efficacy and tropism of exon skipping and surrogate gene therapy. CRISPR-Cas9 has the potential to be a ‘one-hit’ curative treatment in the coming decade. The current limitations of gene editing, such as off-target effects and immunogenicity, are in fact partly constraints of the delivery method itself, and thus research focus has shifted to improving the viral vector. In order to halt the loss of ambulation, early diagnosis and treatment will be pivotal. In an era where genetic sequencing is increasingly utilised in the clinic, genetic therapies will play a progressively central role in DMD therapy. This review delineates the relative merits of cutting-edge genetic approaches, as well as the challenges that still need to be overcome before they become clinically viable.

scholarly journals The administration of antisense oligonucleotide golodirsen reduces pathological regeneration in patients with Duchenne muscular dystrophy

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Dominic Scaglioni ◽  
Francesco Catapano ◽  
Matthew Ellis ◽  
Silvia Torelli ◽  
Darren Chambers ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Antisense Oligonucleotide ◽  
De Novo ◽  
Exon Skipping ◽  
Significant Negative Correlation ◽  
Entire Cohort ◽  
Associated Proteins ◽  
Analysis Platform ◽  
Dystrophin Protein

AbstractDuring the last decade, multiple clinical trials for Duchenne muscular dystrophy (DMD) have focused on the induction of dystrophin expression using different strategies. Many of these trials have reported a clear increase in dystrophin protein following treatment. However, the low levels of the induced dystrophin protein have raised questions on its functionality. In our present study, using an unbiased, high-throughput digital image analysis platform, we assessed markers of regeneration and levels of dystrophin associated protein via immunofluorescent analysis of whole muscle sections in 25 DMD boys who received 48-weeks treatment with exon 53 skipping morpholino antisense oligonucleotide (PMO) golodirsen. We demonstrate that the de novo dystrophin induced by exon skipping with PMO golodirsen is capable of conferring a histological benefit in treated patients with an increase in dystrophin associated proteins at the dystrophin positive regions of the sarcolemma in post-treatment biopsies. Although 48 weeks treatment with golodirsen did not result in a significant change in the levels of fetal/developmental myosins for the entire cohort, there was a significant negative correlation between the amount of dystrophin and levels of regeneration observed in different biopsy samples. Our results provide, for the first time, evidence of functionality of induced dystrophin following successful therapeutic intervention in the human.

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