GEO series

Enhanced antisense oligonucleotide delivery reveals that transcript turnover impacts apparent splicing rescue in myotonic dystrophy

GSE319608 Mus musculus Expression profiling by high throughput sequencing 98 samples Submitted 2026/05/28 Platform GPL30172

Summary

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.

Published in

Shea EN, Olafson HR, Muscato DR et al. · Molecular therapy : the journal of the American Society of Gene Therapy 2026 · PMID 42163456 · doi:10.1016/j.ymthe.2026.04.060

This dataset

Open GSE319608 in finder → Find more mouse RNA-seq datasets →

Download

Direct links to NCBI, no account and no request form: the whole study as GSE319608_RAW.tar, processed values as the series matrix, the supplementary file directory, and per-sample supplementary files for any of the 98 samples. Raw sequencing reads are also available from ENA.

Whole study · RAW.tar ↓ Series matrix ↓ All supplementary files ↗ Raw reads on ENA ↗

Also filed as BioProject PRJNA1424719 and SRA study SRP677638. Searching any of these in the dataset finder brings you back here.

NCBI GEO page ↗ Paper (PMID 42163456) ↗

Study design

9 conditions, mostly with about 4 replicates each

HSALR homozygous, Gastrocnemius, PBS, 7 days, ×8 FVB/NJ, Gastrocnemius, PBS, 7 days, ×4 HSALR homozygous, Gastrocnemius, PMO (30 mg/k… ×4 HSALR homozygous, Gastrocnemius, EEV4-PMO (15… ×4 HSALR homozygous, Gastrocnemius, EEV4-PMO (30… ×4 HSALR homozygous, Gastrocnemius, EEV4-PMO (15… ×4 HSALR homozygous, Gastrocnemius, EEV4-PMO (15… ×4 HSALR homozygous, Gastrocnemius, EEV4-PMO (15… ×4 +1 more

Supports a between-group comparison across 40 samples.

9 replicated groups read from the first 40 of 98 sample titles; they account for 40 of them. Check it against the sample list below before relying on it.

Similar datasets

Search all mouse RNA-seq datasets in GEO →

Share this dataset

Metadata from NCBI GEO, cached and refreshed periodically — the NCBI page above is authoritative. Downloads link straight to NCBI/ENA; nothing is proxied through BioTransfer.