Most mutations in the dystrophin gene create a frameshift or a stop in the mRNA and are associated with severe Duchenne muscular dystrophy. Exon skipping that naturally occurs at low frequency sometimes eliminates the mutation and leads to the production of a rescued protein. We have achieved persistent exon skipping that removes the mutated exon on the dystrophin messenger mRNA of the mdx mouse, by a single administration of an AAV vector expressing antisense sequences linked to a modified U7 small nuclear RNA. We report the sustained production of functional dystrophin at physiological levels in entire groups of muscles and the correction of the muscular dystrophy.

/pdf/rescue-of-dystrophic-muscle-through-u7-snrna-mediated-exon-1i9yk7vq7y.pdf

Rescue of Dystrophic Muscle Through U7 snRNA-Mediated Exon Skipping

Removal of introns from pre-mRNA precursors (pre-mRNA splicing) is a necessary step for the expression of most genes in multicellular organisms, and alternative patterns of intron removal diversify and regulate the output of genomic information. Mutation or natural variation in pre-mRNA sequences, as well as in spliceosomal components and regulatory factors, has been implicated in the etiology and progression of numerous pathologies. These range from monogenic to multifactorial genetic diseases, including metabolic syndromes, muscular dystrophies, neurodegenerative and cardiovascular diseases, and cancer. Understanding the molecular mechanisms associated with splicing-related pathologies can provide key insights into the normal function and physiological context of the complex splicing machinery and establish sound basis for novel therapeutic approaches.

/pdf/the-pathogenicity-of-splicing-defects-mechanistic-insights-2qkd32qlo9.pdf

The pathogenicity of splicing defects: mechanistic insights into pre-mRNA processing inform novel therapeutic approaches

Enhanced Exon-skipping Induced by U7 snRNA Carrying a Splicing Silencer Sequence: Promising Tool for DMD Therapy

Mutation in dystrophin-encoding gene affects energy metabolism in mouse myoblasts

Duchenne muscular dystrophy (DMD) is a severe muscle wasting disorder affecting 1/3500 male births. There is currently no effective treatment, but gene therapy approaches are offering viable avenues for treatment development. The last 10 years have seen the development of a number of strategies and tools for muscle gene therapy. However, the major hurdle has been the inability to deliver vectors at high enough efficiency via a systemic route. The last 2-3 years (reviewed here) have seen unrivalled progress in efficient systemic delivery of viral and non-viral gene transfer agents and antisense oligonucleotides. This progress, coupled with the successful completion of the first gene therapy clinical trial for DMD, has led to three more clinical trials planned for the immediate future.

Gene Therapy Progress and Prospects: Duchenne Muscular Dystrophy

Most cases of Duchenne muscular dystrophy are caused by dystrophin gene mutations that disrupt the mRNA reading frame. Artificial exclusion (skipping) of a single exon would often restore the reading frame, giving rise to a shorter, but still functional dystrophin protein. Here, we analyzed the ability of antisense U7 small nuclear (sn)RNA derivatives to alter dystrophin pre-mRNA splicing. As a proof of principle, we first targeted the splice sites flanking exon 23 of dystrophin pre-mRNA in the wild-type muscle cell line C2C12 and showed precise exon 23 skipping. The same strategy was then successfully adapted to dystrophic immortalized mdx muscle cells where exon-23-skipped dystrophin mRNA rescued dystrophin protein synthesis. Moreover, we observed a stimulation of antisense U7 snRNA expression by the murine muscle creatine kinase enhancer. These results demonstrate that alteration of dystrophin pre-mRNA splicing could correct dystrophin gene mutations by expression of specific U7 snRNA constructs.

U7 snRNAs induce correction of mutated dystrophin pre-mRNA by exon skipping.

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U7 snRNAs induce correction of mutated dystrophin pre-mRNA by exon skipping.