scholarly journals 898. Intracerebral Exon Skipping Restores Dystrophin Expression in CA1 Pyramidal Neurons of mdx Mice

2006 ◽  
Vol 13 ◽  
pp. S346
Author(s):  
Elise Peltekian ◽  
Karine Ros ◽  
Aurelie Goyenvalle ◽  
Carole Gruszczynski ◽  
Cyrille Vaillend ◽  
...  
Keyword(s):  
Pyramidal Neurons ◽  
Exon Skipping ◽  
Mdx Mice ◽  
Ca1 Pyramidal Neurons ◽  
Dystrophin Expression

scholarly journals Nanopolymers improve delivery of exon skipping oligonucleotides and concomitant dystrophin expression in skeletal muscle of mdx mice

2008 ◽  
Vol 8 (1) ◽  
pp. 35 ◽  
Author(s):  
Jason H Williams ◽  
Rebecca C Schray ◽  
Shashank R Sirsi ◽  
Gordon J Lutz
Keyword(s):  
Skeletal Muscle ◽  
Exon Skipping ◽  
Mdx Mice ◽  
Dystrophin Expression

scholarly journals DMD carrier model with mosaic dystrophin expression in the heart reveals complex vulnerability to myocardial injury

2020 ◽  
Vol 29 (6) ◽  
pp. 944-954
Author(s):  
Tatyana A Meyers ◽  
Jackie A Heitzman ◽  
DeWayne Townsend
Keyword(s):  
Myocardial Injury ◽  
Exon Skipping ◽  
Mdx Mice ◽  
Parental Origin ◽  
Wild Type ◽  
Dystrophin Expression ◽  
High Doses ◽  
Therapy Strategies ◽  
Cellular Dysfunction ◽  
Shed Light

Abstract Duchenne muscular dystrophy (DMD) is a devastating neuromuscular disease that causes progressive muscle wasting and cardiomyopathy. This X-linked disease results from mutations of the DMD allele on the X-chromosome resulting in the loss of expression of the protein dystrophin. Dystrophin loss causes cellular dysfunction that drives the loss of healthy skeletal muscle and cardiomyocytes. As gene therapy strategies strive toward dystrophin restoration through micro-dystrophin delivery or exon skipping, preclinical models have shown that incomplete restoration in the heart results in heterogeneous dystrophin expression throughout the myocardium. This outcome prompts the question of how much dystrophin restoration is sufficient to rescue the heart from DMD-related pathology. Female DMD carrier hearts can shed light on this question, due to their mosaic cardiac dystrophin expression resulting from random X-inactivation. In this work, a dystrophinopathy carrier mouse model was derived by breeding male or female dystrophin-null mdx mice with a wild type mate. We report that these carrier hearts are significantly susceptible to injury induced by one or multiple high doses of isoproterenol, despite expressing ~57% dystrophin. Importantly, only carrier mice with dystrophic mothers showed mortality after isoproterenol. These findings indicate that dystrophin restoration in approximately half of the heart still allows for marked vulnerability to injury. Additionally, the discovery of divergent stress-induced mortality based on parental origin in mice with equivalent dystrophin expression underscores the need for better understanding of the epigenetic, developmental, and even environmental factors that may modulate vulnerability in the dystrophic heart.

scholarly journals Massive Idiosyncratic Exon Skipping Corrects the Nonsense Mutation in Dystrophic Mouse Muscle and Produces Functional Revertant Fibers by Clonal Expansion

2000 ◽  
Vol 148 (5) ◽  
pp. 985-996 ◽  
Author(s):  
Q.L. Lu ◽  
G.E. Morris ◽  
S.D. Wilton ◽  
T. Ly ◽  
O.V. Artem'yeva ◽  
...  
Keyword(s):  
Nonsense Mutation ◽  
Exon Skipping ◽  
Dystrophin Gene ◽  
Expression Vectors ◽  
Mdx Mouse ◽  
Mdx Mice ◽  
Functional Protein ◽  
Nonsense Mutations ◽  
Mouse Muscle ◽  
Dystrophin Expression

Conventionally, nonsense mutations within a gene preclude synthesis of a full-length functional protein. Obviation of such a blockage is seen in the mdx mouse, where despite a nonsense mutation in exon 23 of the dystrophin gene, occasional so-called revertant muscle fibers are seen to contain near-normal levels of its protein product. Here, we show that reversion of dystrophin expression in mdx mice muscle involves unprecedented massive loss of up to 30 exons. We detected several alternatively processed transcripts that could account for some of the revertant dystrophins and could not detect genomic deletion from the region commonly skipped in revertant dystrophin. This, together with exon skipping in two noncontiguous regions, favors aberrant splicing as the mechanism for the restoration of dystrophin, but is hard to reconcile with the clonal idiosyncrasy of revertant dystrophins. Revertant dystrophins retain functional domains and mediate plasmalemmal assembly of the dystrophin-associated glycoprotein complex. Physiological function of revertant fibers is demonstrated by the clonal growth of revertant clusters with age, suggesting that revertant dystrophin could be used as a guide to the construction of dystrophin expression vectors for individual gene therapy. The dystrophin gene in the mdx mouse provides a favored system for study of exon skipping associated with nonsense mutations.

scholarly journals Effects of Chronic, Maximal Phosphorodiamidate Morpholino Oligomer (PMO) Dosing on Muscle Function and Dystrophin Restoration in a Mouse Model of Duchenne Muscular Dystrophy

2021 ◽  
pp. 1-13
Author(s):  
Margaret E. Benny Klimek ◽  
Maria Candida Vila ◽  
Katie Edwards ◽  
Jessica Boehler ◽  
James Novak ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Muscle Function ◽  
Imaging Techniques ◽  
Exon Skipping ◽  
Becker Muscular Dystrophy ◽  
Mdx Mice ◽  
High Dose ◽  
Combination Treatments ◽  
Dystrophin Expression

Background: Phosphorodiamidate morpholino oligomer (PMO)-mediated exon skipping is currently used in clinical development to treat Duchenne muscular dystrophy (DMD), with four exon-skipping drugs achieving regulatory approval. Exon skipping elicits a truncated, but semi-functional dystrophin protein, similar to the truncated dystrophin expressed in patients with Becker Muscular dystrophy (BMD) where the disease phenotype is less severe than DMD. Despite promising results in both dystrophic animal models and DMD boys, restoration of dystrophin by exon skipping is highly variable, leading to contradictory functional outcomes in clinical trials. Objective: To develop optimal PMO dosing protocols that result in increased dystrophin and improved outcome measures in preclinical models of DMD. Methods: Tested effectiveness of multiple chronic, high dose PMO regimens using biochemical, histological, molecular, and imaging techniques in mdx mice. Results: A chronic, monthly regimen of high dose PMO increased dystrophin rescue in mdx mice and improved specific force in the extensor digitorum longus (EDL) muscle. However, monthly high dose PMO administration still results in variable dystrophin expression localized throughout various muscles. Conclusions: High dose monthly PMO administration restores dystrophin expression and increases muscle force; however, the variability of dystrophin expression at both the inter-and intramuscular level remains. Additional strategies to optimize PMO uptake including increased dosing frequencies or combination treatments with other yet-to-be-defined therapies may be necessary to achieve uniform dystrophin restoration and increases in muscle function.

Sign in / Sign up

Export Citation Format

Share Document