Abstract
Duchenne muscular dystrophy (DMD) is a fatal disorder characterised by progressive muscle wasting. It is caused by mutations in the dystrophin gene, which disrupt the open reading frame leading to the loss of functional dystrophin protein in muscle fibres. Antisense oligonucleotide (AON)-mediated skipping of the mutated exon, which allows production of a truncated but partially functional dystrophin protein, has been at the forefront of DMD therapeutic research for over two decades. Nonetheless, novel nucleic acid modifications and AON designs are continuously being developed to improve the clinical benefit profile of current drugs in the DMD pipeline. We herein designed a series of 15mer and 20mer AONs, consisting of 2′O-Methyl (2′OMe)- and locked nucleic acid (LNA)-modified nucleotides in different percentage compositions, and assessed their efficiency in inducing exon 23 skipping and dystrophin restoration in locally injected muscles of mdx mice. We demonstrate that LNA/2′OMe AONs with a 30% LNA composition were significantly more potent in inducing exon skipping and dystrophin restoration in treated mdx muscles, compared to a previously tested 2′OMe AON and LNA/2′OMe chimeras with lower or higher LNA compositions. These results underscore the therapeutic potential of LNA/2′OMe AONs, paving the way for further experimentation to evaluate their benefit-toxicity profile following systemic delivery.
Highlights
Duchenne Muscular Dystrophy (DMD) is an X-linked recessive disorder characterised by progressive muscle wasting, loss of ambulation in early adolescence and premature mortality due to cardiorespiratory complications
In order to address the optimal design of chimeric locked nucleic acid (LNA)/20 -OMethyl (20 OMe) Antisense oligonucleotide (AON) for exon skipping activity in vivo, we created a series of 15mer and
An equimolar dose of each AON was injected into the tibialis anterior (TA) muscle of 8-week-old mdx mice and evaluated for exon 23 skipping by RT-PCR, two weeks after treatment
Summary
Duchenne Muscular Dystrophy (DMD) is an X-linked recessive disorder characterised by progressive muscle wasting, loss of ambulation in early adolescence and premature mortality due to cardiorespiratory complications. A milder variant of DMD is Becker Muscular Dystrophy (BMD), caused by deletions in the dystrophin gene that maintain the open reading frame, resulting in the production of a shorter but partially functional dystrophin protein [3]. This variation in the genetic etiology and severity of the two disorders inspired the development of a powerful therapeutic tool, the antisense oligonucleotides (AONs), which induce the skipping of the mutated exon changing the deletion from out-of-frame (severe DMD phenotype) to in-frame (mild BMD phenotype) [4,5,6]. Mutations clustered in exons 43 to 55 can be strategically targeted using multiexon skipping to benefit over 50% of DMD patients, while AON-induced skipping of exon 51 alone can benefit
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