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No more nonsense: evaluating poison exons as therapeutic targets in neurodevelopmental disorders
1Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
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.
Insights
Alternative splicing generates diverse transcripts, sometimes including poison exons (PEs) that trigger decay. Targeting PEs with antisense oligonucleotides (ASOs/SSOs) offers precision therapy for neurodevelopmental disorders.
Area of Science:
- Molecular Biology
- Neuroscience
- Genetics
Background:
- Alternative splicing of pre-mRNA creates transcriptomic diversity.
- Poison exons (PEs) contain premature stop codons (PTCs), targeting transcripts for nonsense-mediated decay (NMD).
- PE-containing transcripts are common in the brain, regulating mRNA and protein levels.
Purpose of the Study:
- To review the role of PEs in the brain.
- To explore therapeutic targeting of PEs using antisense oligonucleotides (ASOs/SSOs).
- To identify current challenges in understanding PEs.
Main Methods:
- Review of existing literature on alternative splicing, PEs, and ASOs/SSOs.
- Analysis of the prevalence and function of PEs in neural tissues.
- Discussion of ASO/SSO-based therapeutic strategies.
Main Results:
- PEs play a significant role in fine-tuning gene expression in the brain.
- ASOs/SSOs are effective in reducing PE inclusion.
- Targeting PEs represents a promising precision medicine approach.
Conclusions:
- Understanding PEs is crucial for developing novel therapies for neurodevelopmental disorders.
- ASOs/SSOs offer a targeted approach to address genetic causes of neurological diseases.
- Further research is needed to overcome current challenges in PE-targeted therapies.
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