Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2025 Jun:92:102346.
doi: 10.1016/j.gde.2025.102346. Epub 2025 Apr 9.

No more nonsense: evaluating poison exons as therapeutic targets in neurodevelopmental disorders

Shreeya Bakshi  1 , Lori L Isom  2
Affiliations
Review

No more nonsense: evaluating poison exons as therapeutic targets in neurodevelopmental disorders

Shreeya Bakshi et al. Curr Opin Genet Dev. 2025 Jun.

Abstract

Alternative splicing of pre-mRNA generates multiple transcripts from a single gene, contributing to transcriptomic diversity. Alternative splicing can result in inclusion of poison exons (PEs), which contain a premature stop codons (PTC) that target transcripts for nonsense-mediated decay (NMD). PE-containing transcripts are prevalent in the brain, where they can play roles in fine-tuning mRNA and protein levels. Antisense, or splice-switching, oligonucleotides (ASOs/SSOs) are used to target PEs to reduce their inclusion and treat neurodevelopmental disorders. ASOs/SSOs address the genetic causes of disease and are precision therapies that can provide a cure rather than only address disease symptoms. This review explores the role of PEs in the brain, therapeutic targeting of PEs, and current challenges in our understanding of PEs.

PubMed Disclaimer

Conflict of interest statement

Declaration of Competing Interest Lori L. Isom reports financial support was provided by University of Michigan Medical School. Lori L. Isom reports a relationship with University of Michigan Medical School that includes funding grants. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

References

    1. Keren H et al. (2010) Alternative splicing and evolution: diversification, exon definition and function. Nat Rev Genet 11, 345–355. 10.1038/nrg2776 - DOI - PubMed
    1. Modrek B and Lee C (2002) A genomic view of alternative splicing. Nat Genet 30, 13–19. 10.1038/ng0102-13 - DOI - PubMed
    1. Lareau LF et al. (2007) Unproductive splicing of SR genes associated with highly conserved and ultraconserved DNA elements. Nature 446, 926–929. 10.1038/nature05676 - DOI - PubMed
    1. Hentze MW and Kulozik AE (1999) A perfect message: RNA surveillance and nonsense-mediated decay. Cell 96, 307–310. 10.1016/s0092-8674(00)80542-5 - DOI - PubMed
    1. Behera A et al. (2024) Nonsense-Mediated mRNA Decay in Human Health and Diseases: Current Understanding, Regulatory Mechanisms and Future Perspectives. Mol Biotechnol. 10.1007/s12033-024-01267-7 - DOI - PubMed

MeSH terms

Substances

LinkOut - more resources