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Nat Med. 2015 Mar;21(3):270-5. doi: 10.1038/nm.3765. Epub 2015 Feb 2.

Functional correction in mouse models of muscular dystrophy using exon-skipping tricyclo-DNA oligomers.

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Université de Versailles St-Quentin, INSERM U1179, LIA BAHN CSM, Montigny-le-Bretonneux, France.
MRC Functional Genomics Unit, University of Oxford, Oxford, UK.
1] Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden. [2] Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
SYNTHENA AG, Bern, Switzerland.
1] Université Paris-Sud, Centre de Neurosciences Paris-Sud, UMR8195, Orsay, France. [2] CNRS, Orsay, France.
Institut de Myologie, Université Pierre et Marie Curie, INSERM U974, CNRS FRE 3217, Paris, France.
Department of Chemistry and Biochemistry, University of Bern, Bern, Switzerland.


Antisense oligonucleotides (AONs) hold promise for therapeutic correction of many genetic diseases via exon skipping, and the first AON-based drugs have entered clinical trials for neuromuscular disorders. However, despite advances in AON chemistry and design, systemic use of AONs is limited because of poor tissue uptake, and recent clinical reports confirm that sufficient therapeutic efficacy has not yet been achieved. Here we present a new class of AONs made of tricyclo-DNA (tcDNA), which displays unique pharmacological properties and unprecedented uptake by many tissues after systemic administration. We demonstrate these properties in two mouse models of Duchenne muscular dystrophy (DMD), a neurogenetic disease typically caused by frame-shifting deletions or nonsense mutations in the gene encoding dystrophin and characterized by progressive muscle weakness, cardiomyopathy, respiratory failure and neurocognitive impairment. Although current naked AONs do not enter the heart or cross the blood-brain barrier to any substantial extent, we show that systemic delivery of tcDNA-AONs promotes a high degree of rescue of dystrophin expression in skeletal muscles, the heart and, to a lesser extent, the brain. Our results demonstrate for the first time a physiological improvement of cardio-respiratory functions and a correction of behavioral features in DMD model mice. This makes tcDNA-AON chemistry particularly attractive as a potential future therapy for patients with DMD and other neuromuscular disorders or with other diseases that are eligible for exon-skipping approaches requiring whole-body treatment.

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