Efficacy and Safety Profile of Tricyclo-DNA Antisense Oligonucleotides in Duchenne Muscular Dystrophy Mouse Model

Abstract : Antisense oligonucleotides (AONs) hold promise for therapeutic splice-switching correction in many genetic diseases. However, despite advances in AON chemistry and design, systemic use of AONs is limited due to poor tissue uptake and sufficient therapeutic efficacy is still difficult to achieve. A novel class of AONs made of tricyclo-DNA (tcDNA) is considered very promising for the treatment of Duchenne muscular dystrophy (DMD), a neuromuscular disease typically caused by frameshifting deletions or nonsense mutations in the gene-encoding dystrophin and characterized by progressive muscle weakness, cardiomyopathy, and respiratory failure in addition to cognitive impairment. Herein, we report the efficacy and toxicology profile of a 13-mer tcDNA in mdx mice. We show that systemic delivery of 13-mer tcDNA allows restoration of dystrophin in skeletal muscles and to a lower extent in the brain, leading to muscle function improvement and correction of behavioral features linked to the emotional/cognitive deficiency. More importantly, tcDNA treatment was generally limited to minimal glomerular changes and few cell necroses in proximal tubules, with only slight variation in serum and urinary kidney toxicity biomarker levels. These results demonstrate an encouraging safety profile for tcDNA, albeit typical of phosphorothiate AONs, and confirm its therapeutic potential for the systemic treatment of DMD patients.
Liste complète des métadonnées

http://hal.upmc.fr/hal-01660493
Contributeur : Alain Perignon <>
Soumis le : dimanche 10 décembre 2017 - 21:10:34
Dernière modification le : jeudi 5 avril 2018 - 10:34:02

Lien texte intégral

Identifiants

Collections

Citation

Karima Relizani, Graziella Griffith, Lucía Echevarría, Faouzi Zarrouki, Patricia Facchinetti, et al.. Efficacy and Safety Profile of Tricyclo-DNA Antisense Oligonucleotides in Duchenne Muscular Dystrophy Mouse Model. Molecular Therapy - Nucleic Acids, Nature Publishing Group, 2017, 8, pp.144 - 157. 〈10.1016/j.omtn.2017.06.013〉. 〈hal-01660493〉

Partager

Métriques

Consultations de la notice

62