Identifying and Avoiding tcDNA-ASO Sequence-Specific Toxicity for the Development of DMD Exon 51 Skipping Therapy.

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 co

SUBMITTER: Aupy P 

PROVIDER: S-EPMC7063478 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature