Functional correction in mouse models of muscular dystrophy using exon-skipping tricyclo-DNA oligomers
| Autor: | Luis Garcia, Kariem Ezzat, Claudia Bühr, Kay E. Davies, Thomas Voit, Christian J. Leumann, Arnaud Ferry, Samir El Andaloussi, Helge Amthor, Stefan Schürch, Aurélie Avril, Graziella Griffith, Aurélie Goyenvalle, Rémi Chaussenot, Arran Babbs, Cyrille Vaillend, Matthew J.A. Wood, Branislav Dugovic |
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| Přispěvatelé: | Handicap neuromusculaire : Physiopathologie, Biothérapie et Pharmacologies appliquées (END-ICAP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), MRC Functional Genomics Unit, Clinical Research Center, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Huddinge, Sweden, Karolinska Institutet [Stockholm]-Karolinska University Hospital [Stockholm], Department of Physiology, Anatomy and Genetics [Oxford], University of Oxford [Oxford], SYNTHENA AG, Institut des Neurosciences Paris-Saclay (NeuroPSI), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Thérapie des maladies du muscle strié, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU), Department of Chemistry and Biochemistry [Bern], University of Bern, Department of Physiology, Anatomy and Genetics, University of Oxford, Medical Research Council Functional Genetics Unit |
| Rok vydání: | 2015 |
| Předmět: |
Pathology
medicine.medical_specialty [SDV]Life Sciences [q-bio] Duchenne muscular dystrophy Nonsense mutation Cardiomyopathy Bioinformatics General Biochemistry Genetics and Molecular Biology Oligodeoxyribonucleotides Antisense Dystrophin Mice Microscopy Electron Transmission medicine Animals RNA Messenger Muscular dystrophy Muscle Skeletal Gene biology Myocardium Heart Exons Genetic Therapy General Medicine medicine.disease Exon skipping 3. Good health Muscular Dystrophy Duchenne Disease Models Animal Blood-Brain Barrier Codon Nonsense biology.protein Systemic administration Nanoparticles Transcriptome |
| Zdroj: | Nature Medicine Nature Medicine, Nature Publishing Group, 2015, 21 (3), pp.270-275. ⟨10.1038/nm.3765⟩ |
| ISSN: | 1546-170X 1078-8956 1744-7933 |
| DOI: | 10.1038/nm.3765 |
| Popis: | International audience; 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. |
| Databáze: | OpenAIRE |
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