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Abstract
Splice modulation therapy has shown great clinical promise in Duchenne muscular dystrophy, resulting in the production of dystrophin protein. Despite this, the relationship between restoring dystrophin to established dystrophic muscle and its ability to induce clinically relevant changes in muscle function is poorly understood. In order to robustly evaluate functional improvement, we used in situ protocols in the mdx mouse to measure muscle strength and resistance to eccentric contraction-induced damage. Here, we modelled the treatment of muscle with pre-existing dystrophic pathology using antisense oligonucleotides conjugated to a cell-penetrating peptide. We reveal that 15% homogeneous dystrophin expression is sufficient to protect against eccentric contraction-induced injury. In addition, we demonstrate a >40% increase in specific isometric force following repeated administrations. Strikingly, we show that changes in muscle strength are proportional to dystrophin expression levels. These data define the dystrophin restoration levels required to slow down or prevent disease progression and improve overall muscle function once a dystrophic environment has been established in the mdx mouse model.
Highlights
The application of antisense oligonucleotide (AO)-based methods to modulate pre-mRNA splicing in Duchenne muscular dystrophy (DMD, OMIM #310200) has placed this monogenic disorder at the forefront of advances in gene therapy
To facilitate the effective delivery of phosphorodiamidate morpholino oligomer (PMO), we undertook a study to directly compare the efficacy of a range of cell-penetrating peptide conjugates, B-PMO [24,25], B-MSP-PMO [26,27], Pip6e-PMO [19] and PMO alone following a dose of 12.5 mg/kg via either an intravenous (IV) or subcutaneous (SC) administration route
The PNAPMO internalization peptide (Pip) series was originally derived from the parent peptide Penetratin [30]
Summary
The application of antisense oligonucleotide (AO)-based methods to modulate pre-mRNA splicing in Duchenne muscular dystrophy (DMD, OMIM #310200) has placed this monogenic disorder at the forefront of advances in gene therapy. Antisense oligonucleotides can be used for targeted exon exclusion resulting in the correction of aberrant reading frames and the production of an internally deleted, yet largely functional, dystrophin protein [2]. The production of dystrophin using AO therapy has been demonstrated in clinical trials [3,4,5,6], the level of internally truncated protein required to provide meaningful clinical improvement in DMD patients is unclear [7]. Studies of patient cohorts with the allelic yet comparatively milder disorders of Becker muscular dystrophy [OMIM 300376] and X-linked cardiomyopathy [OMIM 302045] indicate that sarcolemmal levels of dystrophin as low as 30% are sufficient to avert the onset of symptomatic skeletal muscle degeneration [8,9]
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