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Updated: Jun 9, 2025

Engineering Artificial Factors to Specifically Manipulate Alternative Splicing in Human Cells
Published on: April 26, 2017
Strategies for programmable manipulation of alternative splicing
Jonathan C Schmok1, Gene W Yeo2
1Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA; Sanford Stem Cell Institute Innovation Center and Stem Cell Program, University of California San Diego, La Jolla, CA, USA; Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, USA; Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA.
This review covers four strategies for controlling alternative splicing (AS), including antisense oligonucleotides (ASOs), CRISPR, synthetic factors, and engineered RNAs. These methods offer precise RNA modulation for disease treatment and research.
Area of Science:
- RNA biology
- Molecular biology
- Genetics
Background:
- Alternative splicing (AS) is crucial for generating protein diversity and mRNA maturation.
- Dysregulated splicing is linked to various diseases, making targeted AS control a significant research goal.
Purpose of the Study:
- To review and analyze four primary strategies for programmable manipulation of alternative splicing events.
- To highlight the potential of these strategies in correcting splicing defects and advancing RNA biology.
Main Methods:
- Antisense oligonucleotides (ASOs) to inhibit splicing signals.
- CRISPR-Cas systems for editing splicing signals.
- Synthetic splicing factors (proteins and ribonucleoproteins).
- Bifunctional ASOs and engineered small nuclear RNAs to guide endogenous splicing machinery.
Main Results:
- ASOs are clinically validated for splicing modulation.
- Emerging technologies offer potential for broad, scalable, durable, and precise splicing control.
- These advanced methods promise significant progress in RNA therapeutics.
Conclusions:
- Programmable control of alternative splicing is achievable through diverse strategies.
- Advancements in RNA-based technologies are paving the way for new therapeutic interventions.
- Targeted splicing modulation holds transformative potential for treating genetic diseases.
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