Technologies for Targeted RNA Degradation and Induced RNA Decay
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Updated: Jun 8, 2025
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Published on: December 28, 2016
Sigitas Mikutis1, Gonçalo J L Bernardes1
1Yusuf Hamied Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, U.K.
Abstract:
The vast majority of the human genome codes for RNA, but RNA-targeting therapeutics account for a small fraction of approved drugs. As such, there is great incentive to improve old and develop new approaches to RNA targeting. For many RNA targeting modalities, just binding is not sufficient to exert a therapeutic effect; thus, targeted RNA degradation and induced decay emerged as powerful approaches with a pronounced biological effect. This review covers the origins and advanced use cases of targeted RNA degrader technologies grouped by the nature of the targeting modality as well as by the mode of degradation. It covers both well-established methods and clinically successful platforms such as RNA interference, as well as emerging approaches such as recruitment of RNA quality control machinery, CRISPR, and direct targeted RNA degradation. We also share our thoughts on the biggest hurdles in this field, as well as possible ways to overcome them.
Insights
Targeted RNA degradation offers powerful therapeutic approaches by degrading RNA molecules, moving beyond simple binding. This review explores existing and emerging RNA degrader technologies and their clinical potential.
Area of Science:
- Molecular Biology
- Genetics
- Drug Discovery
Background:
- The human genome is largely transcribed into RNA, yet RNA-targeting drugs remain a small fraction of therapeutics.
- Simple RNA binding is often insufficient for therapeutic effect, necessitating RNA degradation strategies.
Purpose of the Study:
- To review the origins and advanced applications of targeted RNA degrader technologies.
- To categorize these technologies by targeting modality and degradation mechanism.
- To discuss challenges and future directions in RNA-targeting therapeutics.
Main Methods:
- Comprehensive review of established and emerging RNA degradation technologies.
- Classification of methods based on targeting approach and degradation pathway.
- Analysis of clinically successful platforms like RNA interference (RNAi) and novel CRISPR-based systems.
Main Results:
- RNA degradation technologies, including RNA interference, are powerful tools for therapeutic intervention.
- Emerging approaches leverage RNA quality control machinery and CRISPR for targeted degradation.
- Various modalities exist for targeting RNA, with diverse mechanisms for inducing degradation.
Conclusions:
- Targeted RNA degradation represents a significant advancement in RNA-targeting therapeutics.
- Further development is needed to overcome current hurdles in the field.
- Exploring novel degradation mechanisms and delivery systems will be crucial for clinical success.
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