The Dynamics of Compound, Transcript, and Protein Effects After Treatment With 2OMePS Antisense Oligonucleotides in mdx Mice.

摘要: Antisense-mediated exon skipping is currently in clinical development for Duchenne muscular dystrophy (DMD) to amend the consequences of underlying genetic defect and restore dystrophin expression. Due turnover compound, transcript, protein, chronic treatment with effector molecules (antisense oligonucleotides) will be required. To investigate dynamics persistence antisense 2′-O-methyl phosphorothioate oligonucleotides, skipping, expression after dosing was concluded, mdx mice were treated subcutaneously 8 weeks 100 mg/kg oligonucleotides twice weekly. Thereafter, sacrificed at different time points final injection (36 hours–24 weeks). Oligonucleotide half-life longer heart (~65 days) compared that skeletal muscle, liver, kidney (~35 days). Exon half-lives varied between 33 53 days, whereas protein showed a long (>100 exon-skipping levels peaked first week declined thereafter. By contrast, 3–8 then slowly declined, remaining detectable 24 weeks. Concordance proteins observed, except heart, wherein high oligonucleotide but low seen. Overall, these results enhance our understanding pharmacokinetics pharmacodynamics oligos used DMD.