443: 5D‑ASO boosts exon 51 skipping and restores dystrophin in DMD models

Feng P et al., PNAS - This paper describes a bipartite antisense oligonucleotide (5D‑ASO) design that appends a short 5′ splice site decoy tail to improve exon skipping, demonstrating robust efficacy for DMD exon 51 in cells, mice, and cynomolgus monkeys with a favorable safety profile. Key terms: antisense oligonucleotide, exon skipping, Duchenne muscular dystrophy, U1 snRNA decoy, dystrophin restoration.

Study Highlights:
The authors developed a bipartite ASO approach (5D‑ASO) that appends a short 5′ splice site–complementary tail to enhance exon skipping. An optimal 7–8 nt decoy appended to exon 51 ASOs markedly increased exon skipping in human cells and in multiple genetically modified mouse models, restoring dystrophin and improving muscle function. The lead MOE/PS 5D‑ASO showed durable tissue retention, dose‑dependent efficacy, and an overall favorable safety profile in mice and cynomolgus monkeys. The method was operative across multiple genes and exon targets, indicating broad applicability.

Conclusion:
Appending a short 5′ splice site decoy to exon‑targeting ASOs substantially increases exon‑skipping potency and therapeutic benefit in preclinical DMD models, supporting further clinical development of 5D‑ASO designs.

Music:
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Article title:
An antisense method for efficient exon skipping and its application to Duchenne muscular dystrophy

First author:
Feng P

Journal:
PNAS

DOI:
10.1073/pnas.2606494123

Reference:
Feng P., Gao P., Meng S., Yuan Y., Krainer A.R., Hua Y. An antisense method for efficient exon skipping and its application to Duchenne muscular dystrophy. PNAS. 2026;123(33):e2606494123. doi:10.1073/pnas.2606494123

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

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Episode link: https://basebybase.com/episodes/base-by-base-443-5d-aso-dmd

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-08-18.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the core narrative: Duchenne muscular dystrophy background; 5D-ASO design and 5′ splice site decoy tail mechanism; U1 snRNP decoy action; in vitro exon 51 skipping in RD cells; in vivo huEx51/huΔ52 mice data including dystrophin restoration; cynomolgus monkey efficacy/safety; off-target considerations; delivery
- transcript topics: DMD background and dystrophin function; 5D-ASO design and 5′ splice site decoy tail mechanism; U1 snRNP decoy mechanism and splicing repression; In vitro exon skipping in RD cells (Etep-L8c and MOE-Etep); In vivo exon 51 skipping in huEx51/huΔ52 mice and dystrophin restoration; Cynomolgus monkey exon 51 skipping and safety

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 6
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- 5D-ASO tail acts as a decoy to misdirect U1 snRNP...