Molecular correction of Duchenne muscular dystrophy by splice modulation and gene editing

Jan 21, 2021RNA biology

Fixing Duchenne Muscular Dystrophy at the Molecular Level Using RNA Splicing and Gene Editing

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Abstract

Three exon skipping oligonucleotides have received FDA approval for use in treating Duchenne muscular dystrophy (DMD).

DMD is caused by diverse mutations in the dystrophin gene, complicating the development of universal therapies.
Second-generation exon skipping drugs show enhanced potency and can restore dystrophin levels in the heart.
Additional antisense oligonucleotide drugs targeting various exons are currently in clinical development.
Advances in genome engineering, particularly CRISPR/Cas, offer potential new strategies for correcting DMD at the genetic level.
Challenges for clinical application include drug delivery, uniform dystrophin expression, safety concerns, and high treatment costs.

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Duchenne muscular dystrophy (DMD) is a currently incurable X-linked neuromuscular disorder, characterized by progressive muscle wasting and premature death, typically as a consequence of cardiac failure. DMD-causing mutations in the dystrophin gene are highly diverse, meaning that the development of a universally-applicable therapy to treat all patients is very challenging. The leading therapeutic strategy for DMD is antisense oligonucleotide-mediated splice modulation, whereby one or more specific exons are excluded from the mature dystrophin mRNA in order to correct the translation reading frame. Indeed, three exon skipping oligonucleotides have received FDA approval for use in DMD patients. Second-generation exon skipping drugs (i.e. peptide-antisense oligonucleotide conjugates) exhibit enhanced potency, and also induce dystrophin restoration in the heart. Similarly, multiple additional antisense oligonucleotide drugs targeting various exons are in clinical development in order to treat a greater proportion of DMD patient mutations. Relatively recent advances in the field of genome engineering (specifically, the development of the CRISPR/Cas system) have provided multiple promising therapeutic approaches for the RNA-directed genetic correction of DMD, including exon excision, exon reframing via the introduction of insertion/deletion mutations, disruption of splice signals to promote exon skipping, and the templated correction of point mutations by seamless homology directed repair or base editing technology. Potential limitations to the clinical translation of the splice modulation and gene editing approaches are discussed, including drug delivery, the importance of uniform dystrophin expression in corrected myofibres, safety issues (e.g. renal toxicity, viral vector immunogenicity, and off-target gene editing), and the high cost of therapy.

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Molecular correction of Duchenne muscular dystrophy by splice modulation and gene editing

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