ArticleMolecular therapy. Nucleic acids2020
Identifying and Avoiding tcDNA-ASO Sequence-Specific Toxicity for the Development of DMD Exon 51 Skipping Therapy.
Article in Molecular therapy. Nucleic acids, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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18 citing papers in PubMed, 27 citations in OpenAlex.
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- The bench to bedside journey of tricyclo-DNA antisense oligonucleotides for the treatment of Duchenne muscular dystrophy.RSC medicinal chemistry · 2024Review
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- Considerations in the Preclinical Assessment of the Safety of Antisense Oligonucleotides.Nucleic acid therapeutics · 2023Review
- Partial Restoration of Brain Dystrophin and Behavioral Deficits by Exon Skipping in the Muscular Dystrophy X-Linked (mdx) Mouse.Annals of neurology · 2022Article
- Palmitic acid conjugation enhances potency of tricyclo-DNA splice switching oligonucleotides.Nucleic acids research · 2022Article
- Restoring Protein Expression in Neuromuscular Conditions: A Review Assessing the Current State of Exon Skipping/Inclusion and Gene Therapies for Duchenne Muscular Dystrophy and Spinal Muscular Atrophy.BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy · 2021Review
- Delivery of oligonucleotide-based therapeutics: challenges and opportunities.EMBO molecular medicine · 2021Review
- The 10th Oligonucleotide Therapy Approved: Golodirsen for Duchenne Muscular Dystrophy.Nucleic acid therapeutics · 2020Article
- Power and Promise of Next-Generation Sequencing in Liquid Biopsies and Cancer Control.Cancer control : journal of the Moffitt Cancer CenterReview
- An Industry Perspective on Key Considerations for the ICH S13 Guidance: Nonclinical Safety Evaluations of Oligonucleotide-Based Therapeutics.International journal of toxicologyArticle
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Authors and funding
11 authors at 6 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Tricyclo-DNA (tcDNA) antisense oligonucleotides (ASOs) hold promise for therapeutic splice-switching applications and the treatment of Duchenne muscular dystrophy (DMD) in particular. We have previously reported the therapeutic potential of tcDNA-ASO in mouse models of DMD, highlighting their unique pharmaceutical properties and unprecedented uptake in many tissues after systemic delivery, including the heart and central nervous system. Following these encouraging results, we developed phosphorothioate (PS)-modified tcDNA-ASOs targeting the human dystrophin exon 51 (H51). Preliminary evaluation of H51 PS-tcDNA in mice resulted in unexpected acute toxicity following intravenous administration of the selected candidate. In vivo and in vitro assays revealed complement activation, prolonged coagulation times, and platelet activation, correlating with the observed toxicity. In this study, we identify a novel PS-tcDNA sequence-specific toxicity induced by the formation of homodimer-like structures and investigate the therapeutic potential of a detoxified PS-tcDNA targeting exon 51. Modification of the H51-PS-tcDNA sequence, while maintaining target specificity through wobble pairing, abolished the observed toxicity by preventing homodimer formation. The resulting detoxified wobble-tcDNA candidate did not affect coagulation or complement pathways any longer nor activated platelets in vitro and was well tolerated in vivo in mice, confirming the possibility to detoxify specific tcDNA-ASO candidates successfully.
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