{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE319nnn/GSE319608/"]},"type":"primary"},"statusCodeValue":200,"statusCode":"OK"}],"scores":null,"additional":{"omics_type":["Transcriptomics"],"species":["Mus musculus"],"gds_type":["Expression profiling by high throughput sequencing"],"full_dataset_link":["https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE319608"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"Enhanced antisense oligonucleotide delivery reveals that transcript turnover impacts apparent splicing rescue in myotonic dystrophy","description":"Steric-blocking antisense oligonucleotides rescue Myotonic dystrophy type 1 phenotypes in preclinical models and are under evaluation in clinical trials. However, rationale for biomarker selection remains a topic of debate. Here, we show that a cyclic cell-penetrating peptide that escapes endosomes enhances muscle delivery of a phosphorodiamidate morpholino oligonucleotide (PMO) designed to block pathogenic CUG repeat expansions in HSALR mice. A single systemic administration rescued mis-splicing and eliminated myotonia one-week post-injection, with partial splicing rescue evident after 24 hours. Interestingly, some exons showed more robust rescue than others, but relationships between MBNL concentration ([MBNL]) and Percent Spliced In (Ψ) could not fully explain extent of rescue. We hypothesized that since pre-existing transcripts must be degraded to reveal full drug effect, rates of transcript replacement might account for these discrepancies. We formulated a mathematical framework and used Bayesian inference to model how apparent Ψ lags behind nascent Ψ as a function of time; faster rates of replacement result in shorter lags. In vivo 5-ethynyl uridine labeling followed by RNAseq validated these predictions. Overall, we show that transcript turnover influences Ψ during periods of dynamically changing [MBNL] and recommend that this be considered when selecting splicing biomarkers and interpreting responses to therapeutic interventions.","dates":{"publication":"2026/05/28"},"accession":"GSE319608","cross_references":{"GSM":["GSM9521198","GSM9521231","GSM9521199","GSM9521232","GSM9521233","GSM9521234","GSM9521194","GSM9521195","GSM9521196","GSM9521230","GSM9521197","GSM9521239","GSM9521235","GSM9521236","GSM9521237","GSM9521238","GSM9521190","GSM9521191","GSM9521192","GSM9521193","GSM9521242","GSM9521243","GSM9521244","GSM9521245","GSM9521240","GSM9521241","GSM9521246","GSM9521247","GSM9521248","GSM9521249","GSM9521176","GSM9521210","GSM9521177","GSM9521211","GSM9521178","GSM9521179","GSM9521212","GSM9521172","GSM9521173","GSM9521174","GSM9521175","GSM9521217","GSM9521218","GSM9521219","GSM9521213","GSM9521214","GSM9521215","GSM9521216","GSM9521170","GSM9521171","GSM9521187","GSM9521220","GSM9521188","GSM9521221","GSM9521222","GSM9521189","GSM9521223","GSM9521183","GSM9521184","GSM9521185","GSM9521186","GSM9521228","GSM9521229","GSM9521224","GSM9521225","GSM9521226","GSM9521227","GSM9521180","GSM9521181","GSM9521182","GSM9521154","GSM9521155","GSM9521156","GSM9521157","GSM9521158","GSM9521159","GSM9521165","GSM9521166","GSM9521167","GSM9521200","GSM9521201","GSM9521168","GSM9521161","GSM9521162","GSM9521163","GSM9521164","GSM9521206","GSM9521207","GSM9521208","GSM9521209","GSM9521202","GSM9521169","GSM9521203","GSM9521204","GSM9521205","GSM9521160","GSM9521250","GSM9521251"],"GPL":["30172"],"GSE":["319608"],"taxon":["Mus musculus"],"PMID":["[42163456]"]}}