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Related Experiment Video

Updated: May 28, 2025

Engineering Artificial Factors to Specifically Manipulate Alternative Splicing in Human Cells

Engineering Artificial Factors to Specifically Manipulate Alternative Splicing in Human Cells

Published on: April 26, 2017

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).

Keywords:

MT: Oligonucleotides: Therapies and Applications antisense oligonucleotides mixmers nucleic acid chemical modifications nucleic acid therapeutics reporter system splice modulation splice-switching oligonucleotides

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Using the E1A Minigene Tool to Study mRNA Splicing Changes

Using the E1A Minigene Tool to Study mRNA Splicing Changes

Published on: April 22, 2021

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.