New charge-neutral DNA backbones for therapeutics

The latest in a series of papers from the Brown group on new DNA backbones has been published this week.^1–4

Unlike conventional anionic DNA, the team’s new artificial analogues are charge neutral and are designed to improve the uptake of artificial DNA strands into human cells.

Therapeutic oligonucleotides are an emerging class of medicines with the potential to transform the treatment of diseases with no alternative therapies. Several compounds are already in clinical use for diseases such as Duchenne muscular dystrophy and spinal muscular atrophy.

However, their limited therapeutic index – a measure of the margin between an effective dose of a drug and a harmful dose – remains a major obstacle to their wide adoption.

Researchers from Tom Brown’s group at Oxford Chemistry have now created new oligonucleotide backbones and combined them with modified sugars and various ligands. These new compounds greatly increasing the chemical diversity of artificial DNA achievable, and was achieved using just standard solid-phase synthesis.

The new analogues have excellent biophysical properties and show promising activity in cell assays. Encouraged by this, more extensive biological studies are currently underway. Around 200 modified oligonucleotides have been studied and patents have been filed by OUI.

The research was funded by an MRC Consortium grant including the School of Medicine and external academic and industrial partners (https://www.transnat.org.uk/).

1. Dhara, D. et al. Biophysical and biological properties of splice-switching oligonucleotides and click conjugates containing LNA-phosphothiotriester linkages. Nucleic Acids Res. 53 21 (2025). https://doi.org/10.1093/nar/gkaf1263
2. Kennett, A. et al. Synthesis, Biological Activity, and Molecular Dynamics Simulations of LNA-Charge Neutral Linkages for Enhanced Splice-Switching Antisense Oligonucleotides. Angew. Chem. Int. Ed. 64, e202511386 (2025). https://doi.org/10.1002/anie.202511386
3. Dhara, D. et al. Synthesis, Biophysical and Biological Evaluation of Splice-Switching Oligonucleotides with Multiple LNA-Phosphothiotriester Backbones. J. Am. Chem. Soc. 146, 29773–29781 (2024). https://doi.org/10.1021/jacs.4c11402
4. Zengin Kurt, B., Dhara, D., El-Sagheer, A. H. & Brown, T. Synthesis and Properties of Oligonucleotides Containing LNA-Sulfamate and Sulfamide Backbone Linkages. Org. Lett. 26, 19, 4137–4141 (2024). https://doi.org/10.1021/acs.orglett.4c01232