Development of an Antisense Oligonucleotide-Mediated Exon Skipping Therapeutic Strategy for Mucolipidosis II: Validation at RNA Level

2020 ◽  
Vol 31 (13-14) ◽  
pp. 775-783 ◽  
Author(s):  
Liliana Matos ◽  
Regina Vilela ◽  
Melissa Rocha ◽  
Juliana I. Santos ◽  
Maria Francisca Coutinho ◽  
...  
Keyword(s):  
Antisense Oligonucleotide ◽  
Therapeutic Strategy ◽  
Exon Skipping ◽  
Mucolipidosis Ii

scholarly journals Myoblasts and macrophages are required for therapeutic morpholino antisense oligonucleotide delivery to dystrophic muscle

2017 ◽  
Vol 8 (1) ◽  
Author(s):  
James S. Novak ◽  
Marshall W. Hogarth ◽  
Jessica F. Boehler ◽  
Marie Nearing ◽  
Maria C. Vila ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Duchenne Muscular Dystrophy ◽  
Antisense Oligonucleotide ◽  
Antisense Oligonucleotides ◽  
Therapeutic Strategy ◽  
Exon Skipping ◽  
Efficient Production ◽  
Dystrophic Muscle ◽  
Oligonucleotide Delivery ◽  
Dystrophin Protein

Abstract Exon skipping is a promising therapeutic strategy for Duchenne muscular dystrophy (DMD), employing morpholino antisense oligonucleotides (PMO-AO) to exclude disruptive exons from the mutant DMD transcript and elicit production of truncated dystrophin protein. Clinical trials for PMO show variable and sporadic dystrophin rescue. Here, we show that robust PMO uptake and efficient production of dystrophin following PMO administration coincide with areas of myofiber regeneration and inflammation. PMO localization is sustained in inflammatory foci where it enters macrophages, actively differentiating myoblasts and newly forming myotubes. We conclude that efficient PMO delivery into muscle requires two concomitant events: first, accumulation and retention of PMO within inflammatory foci associated with dystrophic lesions, and second, fusion of PMO-loaded myoblasts into repairing myofibers. Identification of these factors accounts for the variability in clinical trials and suggests strategies to improve this therapeutic approach to DMD.

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.

scholarly journals Intravenous Infusion of an Antisense Oligonucleotide Results in Exon Skipping in Muscle Dystrophin mRNA of Duchenne Muscular Dystrophy

2006 ◽  
Vol 59 (5) ◽  
pp. 690-694 ◽  
Author(s):  
Yasuhiro Takeshima ◽  
Mariko Yagi ◽  
Hiroko Wada ◽  
Kazuto Ishibashi ◽  
Atsushi Nishiyama ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Intravenous Infusion ◽  
Antisense Oligonucleotide ◽  
Exon Skipping

T.P.1 05 Antisense oligonucleotide design for therapeutic antisense-mediated exon skipping for Duchenne muscular dystrophy

2006 ◽  
Vol 16 (9-10) ◽  
pp. 686
Author(s):  
A. Aartsma-Rus ◽  
C.L. de Winter ◽  
W.E. Kaman ◽  
A.A.M. Janson ◽  
J.C.T. van Deutekom
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Antisense Oligonucleotide ◽  
Exon Skipping

scholarly journals Antisense oligonucleotide modified with serinol nucleic acid (SNA) induces exon skipping in mdx myotubes

RSC Advances ◽  
2017 ◽  
Vol 7 (54) ◽  
pp. 34049-34052 ◽  
Author(s):  
Bao T. Le ◽  
Keiji Murayama ◽  
Fazel Shabanpoor ◽  
Hiroyuki Asanuma ◽  
Rakesh N. Veedu
Keyword(s):  
Nucleic Acid ◽  
Antisense Oligonucleotide ◽  
Exon Skipping ◽  
Dystrophin Gene ◽  
Gene Transcript

We investigated the potential of SNA-modified antisense oligonucleotide (AO) for exon-skipping. We found that a 20-mer SNA-AO induced efficient exon-23 skipping in the mouse dystrophin gene transcript.

scholarly journals Antisense‐mediated exon skipping: a therapeutic strategy for titin‐based dilated cardiomyopathy

2015 ◽  
Vol 7 (5) ◽  
pp. 562-576 ◽  
Author(s):  
Michael Gramlich ◽  
Luna Simona Pane ◽  
Qifeng Zhou ◽  
Zhifen Chen ◽  
Marta Murgia ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Therapeutic Strategy ◽  
Exon Skipping

scholarly journals Antisense oligonucleotide induced exon skipping and the dystrophin gene transcript: cocktails and chemistries

2007 ◽  
Vol 8 (1) ◽  
pp. 57 ◽  
Author(s):  
Abbie M Adams ◽  
Penny L Harding ◽  
Patrick L Iversen ◽  
Catherine Coleman ◽  
Sue Fletcher ◽  
...  
Keyword(s):  
Antisense Oligonucleotide ◽  
Exon Skipping ◽  
Dystrophin Gene ◽  
Gene Transcript
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