Related Experiment Video
Updated: May 28, 2025
10:06
Engineering Artificial Factors to Specifically Manipulate Alternative Splicing in Human Cells
Published on: April 26, 2017
8.9K
Unveiling sequence-agnostic mixed-chemical modification patterns for splice-switching oligonucleotides using the
Tommaso Tabaglio1, Taniya Agarwal1, Wei Yuan Cher1
1Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A∗STAR), Singapore, Singapore.
Molecular Therapy. Nucleic Acids
|February 10, 2025
Summary
New ribose modifications enhance splice-switching oligonucleotides (SSOs) potency. A novel platform, NATURA, quantifies these enhancements, accelerating the development of nucleic acid therapeutics (NATs).
Area of Science:
- Biochemistry
- Molecular Biology
- Drug Development
Background:
- Chemical modifications of ribose have improved nucleic acid therapeutics (NATs) stability and efficacy.
- Splice-switching oligonucleotides (SSOs) are a class of NATs targeting RNA splicing.
- Optimizing SSO modifications is crucial for enhancing their therapeutic potential.
Purpose of the Study:
- To identify novel chemical modifications that enhance SSO potency.
- To develop a high-throughput platform for quantifying SSO efficacy.
- To accelerate the development and delivery of SSO-based therapies.
Main Methods:
- Investigated mixed-modification patterns of ribose moieties (2'-O-Methyl, 2'-MethOxyEthyl, 2'-Locked Nucleic Acid, and 2'-Constrained Ethyl).
- Developed and validated the NAT Unlabeled Reporter Assay (NATURA) for high-throughput quantification of NAT functional delivery and potency.
- Tested SSO efficacy across various sequences using NATURA in a transgenic mouse model.
Main Results:
- Identified specific mixed-modification patterns, termed lateral mixed positional configuration, that significantly enhance SSO potency.
- Demonstrated improved SSO efficacy across diverse sequences using the novel modification strategy.
- Validated NATURA as a reliable platform for assessing NAT potency and delivery.
Conclusions:
- Lateral mixed positional configuration represents a promising strategy for enhancing SSO efficacy.
- The NATURA platform accelerates the evaluation of NAT modifications and delivery methods.
- These advancements can reduce trial-and-error in SSO development and facilitate NAT delivery to patients.
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