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 disorders1,2. 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 dystrophin3,4 and characterized by progressive muscle weakness, cardiomyopathy, respiratory failure5 and neurocognitive impairment6. 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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We thank P.O. Buclez for technical assistance as well as D. Staunton and the Biophysical Instrumentation Facility at the University of Oxford for help with the SEC-MALS experiment. We also thank S. Vinit, A. Jacquet and N. Mougenot for assistance with the plethysmography and echocardiography experiments, and D. Mornet (INSERM, Montpellier) for the dystrophin-specific primary antibody 5G5. This work was supported by the Agence Nationale de la Recherche (Chair of Excellence HandiMedEx), the Association Monegasque Contre les Myopathies, the Duchenne Parent Project France, the aktion Benni & Co. and the UK Medical Research Council.
Representative decreased ambulation of a 8-week old control dKO mouse. The reduced musculature considerably affects the mobility of the mice, which display a very severe dystrophic phenotype, including contracted and stiff limbs, and very pronounced kyphosis as a result of the degenerative process.
The dystrophic pathology of the treated mouse appears greatly improved as the animal demonstrates only a minimal kyphosis and is very mobile compared to the untreated control.
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Current Treatment Options in Neurology (2018)